Electrical muscle controller

ABSTRACT

A method of modifying the force of contraction of at least a portion of a heart chamber, including providing a subject having a heart, comprising at least a portion having an activation, and applying a non-excitatory electric field having a given duration, at a delay after the activation, to the portion, which causes the force of contraction to be increased by at least 5%.

RELATED APPLICATIONS

[0001] The present application is related to the following U.S. andIsraeli applications, the disclosures of which are incorporated hereinby reference: U.S. provisional application No. 60/009,769, titled“Cardiac Electromechanics”, filed on Jan. 11, 1996, Israel application116,699, titled “Cardiac Electromechanics”, filed on Jan. 8, 1996, U.S.Provisional application No. 60/011,117, titled “Electrical MuscleController”, filed Feb. 5, 1996, Israel application 119,261, titled“Electrical Muscle Controller”, fired Sep. 17, 1996, U.S. Provisionalapplication No. 60/026,392, titled “Electrical Muscle Controller”, filedSep. 16, 1996 and U.S. application Ser. No. 08/595,365 titled “CardiacElectromechanics”, filed Feb. 1, 1996.

FIELD OF THE INVENTION

[0002] The present invention relates to cardiac muscular control, inparticular control using non-excitatory electrical signals.

BACKGROUND OF THE INVENTION

[0003] The heart is a muscular pump whose mechanical activation iscontrolled by electrical stimulation generated at a right atrium andpassed to the entire heart. In a normal heart, the electricalstimulation that drives the heart originates as action potentials in agroup of pacemaker cells lying in a sino-atrial (SA) node in the rightatrium. These action potentials then spread rapidly to both right andleft atria. When the action potential reaches an unactivated musclecell, the cell depolarizes (thereby continuing the spread of the actionpotential) and contracts. The action potentials then enter the heart'sconduction system and, after a short delay, spread through the left andright ventricles of the heart. It should be appreciated that activationsignals are propagated within the heart by sequentially activatingconnected muscle fibers. Each cardiac muscle cell generates a new actionpotential for stimulating the next cell, after a short delay and inresponse to the activation signal which reaches it. Regular electricalcurrents can be conducted in the hear, using the electrolytic propertiesof the body fluids, however, due the relatively large resistance of theheart muscle, this conduction cannot be used to transmit the activationsignal.

[0004] In a muscle cell of a cardiac ventricle, the resting potentialacross its cellular membrane is approximately −90 mV (millivolts) (theinside is negatively charged with respect to the outside). FIG. 1A showsa transmembrane action potential of a ventricle cardiac muscle cellduring the cardiac cycle. When an activation signal reaches one end ofthe cell, a depolarization wave rapidly advances along the cellularmembrane until the entire membrane is depolarized, usually toapproximately +20 mV (23). Complete depolarization of the cell membraneoccurs in a very short time, about a few millisecond. The cell thenrapidly (not as rapid as the depolarization) depolarizes by about 10 mV.After the rapid depolarization, the cell slowly repolarizes by about 20mV over a period of approximately 200-300 msec (milliseconds), calledthe plateau (25). It is during the plateau that the muscle contractionoccurs. At the end of the plateau, the cell rapidly repolarizes (27)back to its resting potential (21). Different cardiac muscle cells havedifferent electrical characteristics, in particular, cells in an SA nodedo not have a substantial plateau and do not reach as low a restingpotential as ventricular cells.

[0005] In the following discussion, it should be appreciated that theexact mechanisms which govern action potentials and ionic pumps andchannels are only partly known. Many theories exist and the field in isa constant state of flux.

[0006] The electrical activity mirrors chemical activity in a cell.Before depolarization (at resting), the concentration of sodium ionsinside the cell is about one tenth the concentration in the interstitialfluid outside the cell. Potassium ions are about thirty-five times moreconcentrated inside the cell than outside. Calcium ions are over tenthousand times more concentrated outside the cell than inside the cell.These concentration differentials are maintained by the selectivepermeability of the membrane to different ions and by ionic pumps in themembrane of the cell which continuously pump sodium and calcium ions outand potassium ions in. One result of the concentration differencesbetween the cell and the external environment is a large negativepotential inside the cell, about 90 mV as indicated above.

[0007] When a portion of the cell membrane is depolarized, such as by anaction potential, the depolarization wave spreads along the membrane.This wave causes a plurality of voltage-gated sodium channels to open.An influx of sodium through these channels rapidly changes the potentialof the membrane from negative to positive (23 in FIG. 1A). Once thevoltage becomes less negative, these channels begin to close, and do notopen until the cell is again depolarizes. It should be noted that thesodium channels must be at a negative voltage of at least a particularvalue in order to be primed for reopening. Thus, these channels cannotbe opened by an activation potential before the cell has sufficientlyrepolarized. In most cells, the sodium channels usually close moregradually than they open. After the rapid depolarization, the membranestarts a fist repolaization process. The mechanism for the fastrepolarization is not fully understood, although closing of the sodiumchannels appears to be an important factor. Following a short phase ofrapid repolarization, a relatively long period (200-300 msec) of slowrepolarization term the plateau stage (25 in FIG. 1A) occurs. During theplateau it is not believed to be possible to initiate another actionpotential in the cell, because the sodium channels are inactivated Twomechanisms appear to be largely responsible for the long duration of theplateau, an inward current of calcium ions and an outward current ofpotassium ions. Both currents flow with their concentration radients,across the membrane. The net result is that the two types of currentelectrically subtract from each other. In general, the flow of potassiumand calcium is many times slower than the flow of the sodium, which isthe reason why the plateau lasts so long. According to some theories,the potassium channels may also open as a result of the actionpotential, however, the probability of a potassium channel opening isdependent on the potential. Thus, many channels open only after thedepolarization of the cell is under way or completed. Possibly, at leastsome of the potassium channels are activated by the calcium ions. Inaddition, some of the potassium channels are triggered by therepolarization of the membrane. The membrane permeability to potassiumgradually increases, following its drop during the rapid depolarization(23). The calcium channels also conduct sodium back into the cell, whichhelps extend the plateau duration.

[0008] The inward calcium current during the normal cardiac actionpotential contributes to the action potential plateau and is alsoinvolved in the contractions (directly and/or indirectly) in the cardiacmuscle cells. In a process termed calcium induced calcium release, theinward current of calcium induces the release of calcium ions stored inintracellular calcium stores (probably the sacroplasmic reticulum). Theexistence and importance of a physical link between the reticulum andthe calcium channels in cardiac muscle is unclear. However, the responsecurve of these calcium stores may be bell-shaped, so that too great aninflux of calcium may reduce the amount of available calcium relative toamount made available by a smaller influx.

[0009] In single cells and in groups of cells, time is required forcells to recover partial and full excitability during the repolarizationprocess. While the cell is repolarizing (25, 27 in FIG. 1A), it enters astate of hyper polarization, during which the cell cannot be stimulatedagain to fire a new action potential. This state is called therefractory period. The refractory period is divided into two parts.During an absolute refractory period, the cell cannot be re-excited byan outside stimulus, regardless of the voltage level of the stimulus.During a relative refractory period, a much larger than usual stimulussignal is required to cause the cell to fire a new action potential. Therefractory state is probably caused by the sodium channels requiringpriming by a negative voltage, so the cell membrane cannot depolarize byflow of sodium ions until it is sufficiently repolarized. Once the cellreturns to its resting potential (21), the cell may be depolarizedagain.

[0010] In an experimental methodology called voltage clamping, anelectrical potential is maintained across at least a portion of a cellmembrane to study the effects of voltage on ionic channels, ionic pumpsand on the reactivity of the cell.

[0011] It is known that by applying a positive potential across themembrane, a cell may be made more sensitive to a depolarization signal.Some cells in the heart, such as the cells in the SA node (the naturalpacemaker of the heart) have a resting potential of about −55 mV. As aresult, their voltage-gated sodium channels are permanently inactivatedand the depolarization stage (23) is slower than in ventricular cells(in general, the action potential of an SA node cell is different fromthat shown in FIG. 1A). However, cells in the SA node have a built-inleakage current, which causes a self-depolarization of the cell on aperiodic basis. In general, it appears that when the potential of a cellstay below about −60 mV for a few msec, the voltage-gated sodiumchannels are blocked. Applying a negative potential across its membranemake a cell less sensitive to depolarization and also hyperpolarizes thecell membrane, which seems to reduce conduction velocity.

[0012] In modern cardiology many parameters of the heart's activationcan be controlled. Pharmaceuticals can be used to control the conductionvelocity, excitability, contractility and duration of the refractoryperiods in the heart. These pharmaceuticals may be used to treatarrhythmias and prevent fibrillations. A special kind of control can beachieved using a pacemaker. A pacemaker is an electronic device which istypically implanted to replace the heart's electrical excitation systemor to bypass a blocked portion of the conduction system. In some typesof pacemaker implantation, portions of the heart's conduction system,for example an atrial-ventricle (AV) node, must be ablated in order forthe pacemaker to operate correctly.

[0013] Another type of cardiac electronic device is a defibrillator. Asan end result of many diseases, the heart may become more susceptible tofibrillation, in which the activation of the heart is substantiallyrandom. A defibrillator senses this randomness and resets the heart byapplying a high voltage impulse(s) to the heart.

[0014] Pharmaceuticals are generally limited in effectiveness in thatthey affect both healthy and diseased segments of the heart, usually,with a relatively low precision. Electronic pacemakers, are fartherlimited in that they are invasive, generally require destruction ofheart tissue and are not usually optimal in their effects.Defibrillators have substantially only one limitation. The act ofdefibrillation is very painful to the patient and traumatic to theheart.

[0015] “Electrical Stimulation of Cardiac Myoctes,” by Ravi Ranjan andNitish V. Thakor, in Annals of Biomedical Engineering, Vol. 23, pp.812-821, published by the Biomedical Engineering Society, 1995, thedisclosure of which is incorporated herein by reference, describesseveral experiments in applying electric fields to cardiac muscle cells.These experiments were performed to test theories relating to electricaldefibrillation, where each cell is exposed to different strengths anddifferent relative orientations of electric fields. One result of theseexperiments was the discovery that if a defibrillation shock is appliedduring repolarization, the repolarization time is extended. In addition,it was reported that cells have a preferred polarization. Cardiac musclecells tend to be more irregular at one end than at the other. It istheorized, in the article, that local “hot spots” of high electricalfields are generated at these irregularities and that these “hot spots”are the sites of initial depolarization within the cell, since it is atthese sites that the threshold for depolarization is first reached. Thistheory also explains another result, namely that cells are moresensitive to electric fields in their longitudinal direction than intheir transverse direction, since the irregularities are concentrated atthe cell ends. In addition, the asymmetric irregularity of the cells mayexplain results which showed a preferred polarity of the appliedelectric field.

[0016] The electrical activation of skeleton muscle cells is similar tothat of cardiac cells in that a depolarization event induces contractionof muscle fibers. However, skeleton muscle is divided into isolatedmuscle bundles, each of which is individually enervated by actionpotential generating nerve cells. Thus, the effect of an actionpotential is local, while in a cardiac muscle, where all the musclecells are electrically connected, an action potential is transmitted tothe entire heart from a single loci of action potential generation. Inaddition, the chemical aspects of activation of skeletal muscle issomewhat different from those of cardiac muscle.

[0017] “Muscle Recruitment with Infrafascicular Electrodes”, by NicolaNannini and Kenneth Horch, IEEE Transactions on Biomedical Engineering,Vol. 38, No. 8, pp. 769-776, August 1991, the disclosure of which isincorporated herein by reference, describes a method of varying thecontractile force of skeletal muscles, by “recruiting” a varying numberof muscle fibers. In recruiting, the contractile force of a muscle isdetermined by the number of muscle fibers which are activated by astimulus.

[0018] However, it is generally accepted that cardiac muscle fibersfunction as a syncytium such that each and every cell contracts at eachbeat. Thus, there are no cardiac muscles fibers available forrecruitment. See for example, “Excitation Contraction Coupling andCardiac Contractile Force”, by Donald M. Bers, Chapter 2, page 17,Kluwer Academic, 1991, the disclosure of which is incorporated herein byreference. This citation also states that in cardiac muscle cells,contractile force is varied in large part by changes in peak calcium.

[0019] “Effect of Field Stimulation on Cellular Repolarization in RabbitMyocardium”, by Stephen B. Knisley, William M. Smith and Raymond E.Ideker, Circulation Research, Vol. 70, No. 4, pp. 707-715, April 1992,the disclosure of which is incorporated herein by reference, describesthe effect of an electrical field on rabbit myocardium. In particular,this article describes prolongation of an action potential as a resultof a defibrillation shock and ways by which this effect can causedefibrillation to fail. One hypothesis is that defibrillation affectscardiac cells by exciting certain cells which are relatively lessrefractory than others and causes the excited cells to generate a newaction potential, effectively increasing the depolarization time.

[0020] “Optical Recording in the Rabbit Heart Show That DefibrillationStrength Shocks Prolong the Duration of Depolarization and theRefractory Period”, by Stephen M. Dillon, Circulation Research, Vol. 69,No. 3, pp. 842-856, September, 1991, the disclosure of which isincorporated herein by reference, explains the effect of prolongedrepolarization as caused by the generation of a new action potential inwhat was thought to be refractory tissue as a result of thedefibrillation shock. This article also proves experimentally that suchan electric shock does not damage the cardiac muscle tissue and that theeffect of a second action potential is not due to recruitment ofpreviously unactivated muscle fibers. It is hypothesized in this articlethat the shocks hyperpolarize portions of the cellular membrane and thusreactivate the sodium channels. In the experiments described in thisarticle, the activity of calcium channels is blocked by the applicationof methoxy-verapamil.

[0021] “Electrical Resistances of Interstitial and Microvascular Spaceas Determinants of the Extracellular Electrical field and Velocity ofPropagation in Ventricular Myocardium”, by Johannes Fleischhauer, LillyLehmann and Andre G. Kleber, Circulation, Vol. 92, No. 3, pp. 587-594,Aug. 1, 1995, the disclosure of which is incorporated herein byreference, describes electrical conduction characteristics of cardiacmuscle.

[0022] “Inhomogeneity of Cellular Activation Time and-Vmax in NormalMyocardial Tissue Under Electrical Field Stimulation”, by AkihikoTaniguchi, Junji Toyama, Itsuo Kodama, Takafumi Anno, Masaki Shirakawaand Shiro Usui, American Journal of Physiology, Vol. 267 (HeartCirculation Physiology, Vol. 36), pp. H694-H705, 1994, the disclosure ofwhich is incorporated herein by reference, describes variousinteractions between electro-tonic currents and action potentialupstrokes.

[0023] “Effect of Light on Calcium Transport in Bull Sperm Cells”, by R.Lubart, H. Friedmann, T. Levinshal, R. Lavie and H. Breitbart, Journalof Photochemical Photobiology B, Vol. 14, No. 4, pp. 337-341, Sep. 12,1992, the disclosure of which is incorporated herein by reference,describes an effect of light on bull sperm cells, in which laser lightincreases the calcium transport in these cells. It is also known thatlow level laser light affects calcium transport in other types of cells,for example as described in U.S. Pat. No. 5,464,436, the disclosure ofwhich is incorporated herein by reference.

[0024] The ability of electromagnetic radiation to affect calciumtransport in cardiac myocytes is well documented. Loginov V A,“Accumulation of Calcium Ions in Myocardial Sarcoplasmic Reticulum ofRestrained Rats Exposed to the Pulsed Electromagnetic Field”, inAviakosm Ekolog Med, Vol. 26, No. 2, pp. 49-51, March-April, 1992, thedisclosure of which is incorporated herein by reference, describes anexperiment in which rats were exposed to a 1 Hz field of between 6 and24 mTesla After one month, a reduction of 33 percent in the velocity ofcalcium accumulation was observed. After a second month, theaccumulation velocity was back to normal, probably due to an adaptationmechanism.

[0025] Schwartz J L, House D E and Mealing G A, in “Exposure of FrogHearts to CW or Amplitude-Modulated VHF Fields: Selective Efflux ofCalcium Ions at 16 Hz”, Bioelectromagnetics, Vol. 11, No. 4, pp.349-358, 1990, the disclosure of which is incorporated herein byreference, describes an experiment in which the efflux of calcium ionsin isolated frog hearts was increased by between 18 and 21% by theapplication of a 16 Hz modulated VHF clectromagnetic field.

[0026] Lindstrom E, Lindstrom P, Berglund A, Lundgren E and Mild K H, in“Intracellular Calcium Oscillations in a T-cell Line After Exposure toExtremely-Low-Frequency Magnetic Fields with Variable Frequencies andFlux Densities”, Bioelectromagnetics, Vol. 16, No. 1, pp. 4147, 1995,the disclosure of which is incorporated herein by reference, describesan experiment in which magnetic fields, at frequency between 5 and 100Hz (Peak at 50 Hz) and with intensities of between 0.04 and 0.15 mTeslaaffected calcium ion transport in T-cells.

[0027] Loginov V A, Gorbatenkova N V and Klimovitksi Vla, in “Effects ofan Impulse Electromagnetic Field on Calcium Ion Accumulation in theSarcoplasmatic Reticulum of the Rat Myocardium”, Kosm Biol Aviakosm Med,Vol. 25, No. 5, pp. 51-53, September-October, 1991, the disclosure ofwhich is incorporated herein by reference, describes an experiment inwhich a 100 minute exposure to a 1 msec impulse, −10 Hz frequency and1-10 mTesla field produced a 70% inhibition of calcium transfer acrossthe sarcoplasmic reticulum. The effect is hypothesized to be associatedwith direct inhibition of Ca-ATPase.

[0028] It should be noted that some researchers claim that low frequencymagnetic fields do NOT have the above reported effects. For example,Coulton L A and Barker A T, in “Magnetic Fields and IntracellularCalcium: Effects on Lymphocytes Exposed to Conditions for ‘CyclotronResonance’”, Phys Med Biol, Vol. 38, No. 3, pp. 347-360, March, 1993,the disclosure of which is incorporated herein by references, exposedlymphocytes to radiation at 16 and 50 Hz, for a duration of 60 minutesand filled to detect any changes in calcium concentration.

[0029] Pumir A, Plaza F and Krinsky V I, in “Control of Rotating Wavesin Cardiac Muscle: Analysis of the Effect of Electric Fields”, Proc RSoc Lond B Biol Sci, Vol. 257, No. 1349, pp. 129-34, Aug. 22, 1994, thedisclosure of which is incorporated herein by reference, describes thatan application of an external electric field to cardiac muscle affectsconduction velocity by a few percent. This effect is due to thehyperpolarization of one end of muscle cells and a depolarization of theother end of the cell. In particular, an externally applied electricfield favors propagation antiparallel to it. It is suggested in thearticle to use this effect on conduction velocity to treat arrhythmiasby urging rotating waves, which are the precursors to arrhythmias, todrift sideways to nonexcitable tissue and die. “Control of MuscleContractile Force Through Indirect High-Frequency Stimulation”, by M.Sblomonow, E. Eldred, J. Lyman and J. Foster, American Journal ofPhysical Medicine, Vol. 62, No. 2, pp. 71-82, April 1983, the disclosureof which is incorporated herein by reference, describes a method ofcontrolling skeletal muscle contraction by varying various parameters ofa 500 Hz pulse of electrical stimulation to the muscle.

[0030] “Biomedical Engineering Handbook”, ed. Joseph D. Bronzino,chapter 82.4, page 1288, IEEE press/CRC press, 1995, describes the useof precisely timed subthreshold stimuli, simultaneous stimulation atmultiple sites and pacing with elevated energies at the site of atachycardia foci, to prevent tachycardia. However, none of these methodshad proven practical at the time the book was written. In addition abiphasic defibrillation scheme is described and it is theorized thatbiphasic defibrillation scheme are more effective by virtue of a largervoltage change when the phase changes or by the biphasic waveformcausing hyperpolarization of tissue and reactivation of sodium channels.

[0031] “Subthreshold Conditioning Stimuli Prolong Human VentricularRefactoriness”, Windle J R, Miles W M, Zipes D P and Prystowsky E N,American Journal of Cardiology, Vol. 57, No. 6, pp. 381-386, February,1986, the disclosure of which is incorporated herein by reference,describes a study in which subthreshold stimuli were applied before apremature stimulus and effectively blocked the premature stimulus fromhaving a pro-arrhythmic effect by a mechanism of increasing therefractory period of right ventricular heart tissue.

[0032] “Ultrarapid Subthreshold Stimulation for Termination ofAtrioventlicular Node Reentrant Tachycardia”, Fromer M and Shenasa M,Journal of the American Collage of Cardiology, Vol. 20, No. 4, pp.879-883, October, 1992, the disclosure of which is incorporated hereinby reference, describes a study in which trains of subthreshold stimuliwere applied asynchronously to an area near a reentry circuit andthereby terminated the arrhythmia. Subthreshold stimuli were describedas having both an inhibitory and a facilitating effect on conduction. Inaddition, subthreshold stimuli are described as reducing the thresholdof excitability, possibly even causing an action potential.

[0033] “Inhibition of Premature Ventricular Extrastimuli by SubthresholdConditioning Stimuli”, Skale B, Kallok M J, Prystowsky E N, Gill R M andZipes D P, Journal of the American Collage of Cardiology, Vol. 6, No. 1,pp. 133-140, July, 1985, the disclosure of which is incorporated hereinby reference, describes an animal study in which a train of 1 msecduration pulses were applied to a ventricle 2 msec before a prematurestimuli, inhibited the response to the premature stimuli, with a highfrequency train delaying the response for a much longer amount of time(152 msec) than a single pulse (20 msec). The delay between the pacingof the ventricle and the pulse train was 75 msec. However, thesubthreshold stimuli only had this effect when delivered to the samesite as the premature stimulus. It is suggested to use a subthresholdstimuli in to prevent or terminate tachycardias, however, it is notedthat this suggestion is restrained by the spatial limitation of thetechnique.

[0034] “The Phase of Supernormal Excitation in Relation to the Strengthof Subthreshold Stimuli”, Yokoyama M, Japanese Heart Journal, Vol. 17,No. 3, pp. 35-325, May, 1976, the disclosure of which is incorporatedherein by reference, describes the effect of varying the amplitude of asubthreshold stimuli on supernormal excitation. When the amplitude ofthe stimuli was increased, the supernormal excitation phase increased inlength.

SUMMARY OF THE INVENTION

[0035] It is an object of some aspects of the present invention toprovide a method of locally controlling the electrical and/or mechanicalactivity of cardiac muscle cells, in situ. Preferably, continuouscontrol is applied. Alternatively, discrete control is applied. Furtherpreferably, the control may be varied between cardiac cycles. Oneexample of electrical control is shortening the refractory period of amuscle fiber by applying a negative voltage to the outside of the cell.The cell may also be totally blocked from reacting by maintaining asufficiently positive voltage to the outside of the cell, so that anactivation signal fails to sufficiently depolarize the cellularmembrane. One example of mechanical control includes increasing ordecreasing the strength of contraction and the duration of thecontraction. This may be achieved by extending or shortening the plateauand/or the action potential duration by applying non-excitatory voltagepotentials across the cell. The increase in strength of contraction mayinclude an increase in peak force of contraction attained by musclefibers, may be an increase in an average force of contraction, bysynchronization of contraction of individual fibers or may includechanging the timing of the peak strength.

[0036] It should be appreciated that some aspects of the presentinvention are different from both pacemaker operation and defibrillatoroperation. A pacemaker exerts excitatory electric fields for manycycles, while a defibrillator does not repeat its applied electric fieldfor man, cycles, due to the disruptive effect of the defibrillationcurrent on cardiac contraction. In fact, the main effect of thedefibrillation current is to reset the sychronization of the heart byforcing a significant percentage of the cardiac tissue into a refractorystate. Also, defibrillation currents are several orders of magnitudestronger than pacing currents. It is a particular aspect of someembodiments of the present invention that the regular activation of theheart is not disrupted, rather, the activation of the heart iscontrolled, over a substantial number of cycles, by varying parametersof the reactivity of segments of cardiac muscle cell.

[0037] In some aspects of the invention, where the hear is artificiallypaced in addition to being controlled in accordance with the presentinvention, the activation cycle of the heart is normal with respect tothe pacing. For example, when the control is applied locally, such thatthe activation of the rest of the heart is not affected.

[0038] In some aspect of the invention, the control is initiated as aresponse to an unusual cardiac event, such as the onset of fibrillationor the onset of various types of arrhythmias. However, in other aspectsof the present invention, the control is initiated in response to adesired increase in cardiac output or other long-term effects, such asreducing the probability of ventricular fibrillation (VF) or increasingthe coronary blood flow.

[0039] Another difference between defibrillation, pacing and someembodiments of the present invention is that defibrillation and pacingare applied as techniques to affect the entire heart (or at least anentire chamber), while certain embodiments of the present invention, forexample, fences (described below), are applied to local portion of theheart (which may be as large as an entire chamber) with the aim ofaffecting only local activity. Yet another difference between someembodiment of the present invention and defibrillation is in the energyapplied to the heart muscle. In defibrillation, a typical electric fieldstrength is 0.5 Joule (which is believed to be strong enough to exciterefractory tissue, “Optical Recordings . . . ” cited above), while invarious embodiment of the invention, the applied field strength isbetween 50 and 500 micro joules, a field strength which is believed tonot cause action potentials in refractory tissue.

[0040] It is a further object of some aspects of the present inventionto provide a complete control system for the heart which includes, interalia, controlling the pacing rate, refractory period, conductionvelocity and mechanical force of the heart. Except for heart rate, eachof these parameters may be locally controlled, i.e., each parameter willbe controlled in only a segment of cardiac muscle. It should be notedthat heart rate may also be locally controlled, especially with the useof fences which isolate various heart segments from one another,however, in most cases this is detrimental to the heart's pumpingefficiency.

[0041] In one preferred embodiment of the present invention, electricaland/or mechanical activity of a segment of cardiac muscle is controlledby applying a non-exciting field (voltage) or current across thesegment. A non-exciting signal may cause an existing action potential tochange, but it will not cause a propagating action potential, such asthose induced by pacemakers. The changes in the action potential mayinclude extension of the plateau duration, extension of the refractoryperiod, shortening of the post-plateau repolarization and other changesin the morphology of the action potential. However, the non-excitingsignal may affect a later action potential for example, it may delaysuch a potential or may accelerate its onset. Another type ofnon-exciting signal is a voltage which does not cause a new contractionof the cardiac muscle cell to which the non-exciting signal is applied.Activation potential generation may be averted either by applyingvoltage of the wrong polarity, the voltage being applied when the celland/or the surrounding cells are not sensitive to it or by the amplitudeof the voltage being too small to-depolarize the cell to the extent thata new action potential will be generated during that period.

[0042] Optionally, this control is exerted in combination with apacemaker which applies an exciting signal to the heart. In a preferredembodiment of the invention, a pacemaker (or a defibrillator)incorporates a controller, operating in accordance with at least oneembodiment of the invention. A pacemaker and a controller may share abattery, a micro-controller, sensors and possibly electrodes.

[0043] In another preferred embodiment of the present invention,arrhythmias and fibrillation are treated using fences. Fences aresegments of cardiac muscle which are temporarily inactivated usingelectrical fields. In one example, atrial fibrillation is treated bychanneling the activation signal from an SA node to an AV node byfencing it in. In another example, fibrillations are damped by fencingin the multitude of incorrect activation signals, so that only one pathof activation is conducting. In still another example, ventriculartachycardia or fibrillation is treated by dividing the heart intoinsulated segments, using electrical fields and deactivating the fencesin sequence with a normal activation sequence of the heart, so that atmost only one segment of the heart will be prematurely activated.

[0044] In still another preferred embodiment of the invention, themuscle mass of the heart is redistributed using electrical fields. Ingeneral, changing the workload on a segment of cardiac muscle activatesadaptation mechanisms which tend to change the muscle mass of thesegment with time. Changing the workload may be achieved, in accordancewith a preferred embodiment of the invention, by increasing ordecreasing the action potential plateau duration of the segment, usingapplied electrical fields. Alternatively or additionally, the workloadmay be changed indirectly, in accordance with a preferred embodiment ofthe invention, by changing the activation time of the segment of theheart and/or its activation sequence. Further additionally ofalternatively, the workload may be changed by directly controlling thecontractility of a segment of the heart.

[0045] In yet another preferred embodiment of the invention, theoperation of the cardiac pump is optimized by changing the activationsequence of the heart and/or by changing plateau duration at segments ofthe heart and/or by changing the contractility thereat.

[0046] In still another preferred embodiment of the invention, thecardiac output is modified, preferably increased, by applying anon-excitatory electric field to a segment of the heart, preferably theleft ventricle. Preferably, the extent of increase in cardiac output,especially the left ventricular output, is controlled by varying thesize of the segment of the heart to which such a field is applied.Alternatively or additionally, the strength of the electric field ischanged. Alternatively or additionally, the timing of the pulse ischanged. Alternatively or additionally, the duration, shape or frequencyof the pulse is changed. The increase in output may include an increasein peak flow rate, in flow volume, in average flow rate, or it mayinclude a change in the flow profile, such as a shift in the developmentof the peak flow, which improves overall availability of blood to bodyorgans.

[0047] In still another preferred embodiment of the invention, thedeveloped ventricular pressure is modified, preferably increased, byapplying a non-excitatory electric field to a segment of the heart,preferably the left ventricle. Preferably, the extent of increase incardiac output is controlled by varying the size of the segment of theheart to which such a field is applied. Alternatively or additionally,the strength of the electric field is changed. Alternatively oradditionally, the timing of the pulse is changed. Alternatively oradditionally, the duration of the pulse is changed. Alternatively oradditionally, the waveform of the pulse is changed. Alternatively oradditionally, the frequency of the pulse is changed. The increase inpressure may include an increase in peak pressure, average pressure orit may include a change in the pressure profile, such as a shift in thedevelopment of the peak pressure, which improves the contractility.

[0048] In accordance with yet another preferred embodiment of theinvention, the afterload of the heart is increased by applyingnon-excitatory electric fields to at least a segment of the heart,whereby the flow in the coronary arteries is improved.

[0049] In accordance with another preferred embodiment of the inventionvarious cardiac parameters are controlled via inherent cardiac feedbackmechanisms. In one example, the heart rate is controlled by applying anon-exciting voltage to pacemaker cells of the heart, at or near the SAnode of the heart. Preferably, the heart rate is increased by applyingthe non excitatory field.

[0050] In a preferred embodiment of the invention, a single field isapplied to a large segment of the heart. Preferably, the field isapplied at a time delay after the beginning of the systole. Preferably,the non-exciting field is stopped before half of the systole is over, toreduce the chances of fibrillation.

[0051] In another preferred embodiment of the invention, a plurality ofsegments of the heart are controlled, each with a differentnon-excitatory electric field. Preferably, each electric field issynchronized to the local activation or other local parameters, such asinitiation of contraction. A further preferred embodiment of theinvention takes into account the structure of the heart. The heartmuscle is usually disposed in layers, with each layer having a(different) muscle fiber orientation. In this embodiment of theinvention, a different field orientation and/or polarity is preferablyapplied for different orientations of muscle fibers.

[0052] In one preferred embodiment of the invention, this technique,which takes the muscle fiber orientation into account, may be applied tolocal defibrillation-causing electric fields, the purpose of whichfields may be to delay the repolarization of a certain, limited segmentof the heart, thereby creating a fence.

[0053] There is therefore provided in accordance with a preferredembodiment of the invention, a method of modifying the force ofcontraction of at least a portion of a heart chamber, comprising:

[0054] providing a subject having a heart, comprising at least a portionhaving an activation; and

[0055] applying a non-excitatory electric field having a given duration,at a delay after the activation, to the portion, which causes the forceof contraction to be increased by at least 5%.

[0056] Preferably, the force is increased by a greater percentage suchas at least 10%, 30% or 50%

[0057] There is further provided, in accordance with a preferredembodiment of the invention a method of modifying a force of contractionof at least a portion of a heart chamber, comprising:

[0058] providing a subject having a heart, comprising at least a portionhaving an activation; and

[0059] applying a non-excitatory electric field having a given duration,to the portion at a delay of less than 70 msec after the activation.

[0060] There is further provided, in accordance with a preferredembodiment of the invention a method of modifying the force ofcontraction of at least a portion of a heart chamber, comprising:

[0061] providing a subject having a heart, comprising at least a portionhaving an activation; and

[0062] applying a non-excitatory electric field having a given duration,at a delay after the activation, to the portion, which causes thepressure in the chamber to be increased by at least 2%.

[0063] Preferably the pressure is increased by a greater amount such asat least 10% or 20%.

[0064] There is further provided in accordance with a preferredembodiment of the invention a method of modifying the force ofcontraction of at least a portion of a heart chamber, comprising:

[0065] providing a subject having a heart, comprising at least a portionhaving an activation; and

[0066] applying a non-excitatory electric field having a given duration,at a delay after the activation, to the portion, wherein the chamber hasa flow volume and wherein the flow volume is increased by at least 5%.

[0067] Preferably, the flow volume is increased by a greater amount suchas at least 10% or 20%.

[0068] There is further provided, in accordance with a preferredembodiment of the invention a method of modifying the force ofcontraction of at least a portion of a heart chamber. comprising:

[0069] providing a subject having a heart, comprising at least a portionhaving an activation; and

[0070] applying a non-excitatory electric field having a given duration,at a delay after the activation, to the portion, wherein the chamber hasa flow rate such that the flow rate is increased by at least 5%.

[0071] Preferably, the flow rate is increased by a greater amount suchas at least 10% or 20%.

[0072] There is further provided, in accordance with a preferredembodiment of the invention a method of modifying the force ofcontraction of at least a portion of a heart chamber, comprising:

[0073] providing a subject having a heart, comprising at least a portionhaving an activation; and

[0074] applying a non-excitatory electric field to the portion at adelay after the activation, the field having a given duration of atleast 101 msec and not lasting longer than the cycle length. Preferablythe duration is longer, such as at least 120 sec or 150 msec.

[0075] There is further provided, in accordance with a preferredembodiment of the invention a method of modifying a force of contractionof at least a portion of a heart chamber, comprising:

[0076] providing a subject having a heart, comprising at least a portionhaving an activation; and

[0077] applying a non-excitatory electric field having a given duration,at a delay after the activation, to the portion,

[0078] wherein the portion of the chamber has an inner surface and anouter surface and wherein the field is applied between the inner surfaceand the outer surface.

[0079] There is further provided, in accordance with a preferredembodiment of the invention a method of modifying a force of contractionof at least a portion of a heart chamber, comprising:

[0080] providing a subject having a heart, comprising at least a portionhaving an activation; and

[0081] applying a non-excitatory electric field having a given duration,at a delay after the activation, to the portion,

[0082] wherein the portion of the chamber has an inner surface and anouter surface and wherein the field is applied along the outer surface.

[0083] There is further provided, in accordance with a preferredembodiment of the invention a method of modifying a force of contractionof at least a portion of a heart chamber, comprising:

[0084] providing a subject having a heart comprising at least a portionhaving an activation; and

[0085] applying a non-excitatory electric field having a given duration,at a delay after the activation, to the portion,

[0086] wherein the portion of the chamber has an inside surface, anoutside surface and an intra-muscle portion and wherein the field isapplied between the intra-muscle portion and at least one of thesurfaces.

[0087] There is further provided, in accordance with a preferredembodiment of the invention a method of modifying a force of contractionof at least a portion of a heart chamber, comprising:

[0088] providing a subject having a hear comprising at least a portionhaving an activation; and

[0089] applying a non-excitatory electric field having a given duration,at a delay after the activation, to the portion,

[0090] wherein the field is applied between a single electrode and acasing of an implanted device.

[0091] There is further provided, in accordance with a preferredembodiment of the invention a method of modifying a force of contractionof at least a portion of a heart chamber, comprising:

[0092] providing a subject having a heart comprising at least a portionhaving an activation; and

[0093] applying a non-excitatory electric field having a given duration,at a delay after the activation, to the portion, using an electrodefloating inside the heart.

[0094] There is further provided, in accordance with a preferredembodiment of the invention a method of modifying a force of contractionof at least a portion of a heart chamber, comprising:

[0095] providing a subject having a heart, comprising at least a portionhaving an activation; and

[0096] applying a non-excitatory electric field having a given duration,at a delay after the activation, to the portion,

[0097] wherein the field is applied using at least two electrodes andwhen the at least two electrodes are at least 2 cm apart.

[0098] In preferred embodiments of the invention the electrodes are atleast 4 or 9 cm apart.

[0099] There is further provided, in accordance with a preferredembodiment of the invention a method of modifying a force of contractionof at least a portion of a heart chamber, comprising:

[0100] providing a subject having a heart, comprising at least a portionhaving an activation; and

[0101] applying a non-excitatory electric field having a given duration,at a delay after the activation, to the portion,

[0102] wherein the field is applied using at least two electrodes andwherein one electrode of the at least two electrodes is at a base of achamber of the heart and one electrode is at an apex of a chamber of theheart.

[0103] There is further provided, in accordance with a preferredembodiment of the invention a method of modifying a force of contractionof at least a portion of a heart chamber, comprising:

[0104] providing a subject having a heart, comprising at least a portionhaving an activation; and

[0105] applying a non-excitatory electric field having a given duration,at a delay after the activation, to the portion,

[0106] wherein the field is applied using at least three electrodes andwherein applying a non-excitatory field comprises:

[0107] electrifying a first pair of the at least three electrodes; and

[0108] subsequently electrifying a second pair of the at least threeelectrodes.

[0109] There is further provided, in accordance with a preferredembodiment of the invention a method of modifying a force of contractionof at least a portion of a heart chamber, comprising:

[0110] providing a subject having a heart, comprising at least a portionhaving an activation; and

[0111] applying a non-excitatory electric field having a given duration,at a delay after the activation, to the portion, wherein the field isapplied using at least two electrodes placed externally to the subject.

[0112] There is further provided, in accordance with a preferredembodiment of the invention a method of modifying a force of contractionof at least a portion of a heart chamber, comprising:

[0113] providing a subject having a heart, comprising at least a portionhaving an activation; and

[0114] applying a non-excitatory electric field having a given duration,at a delay after the activation, to the portion,

[0115] wherein the electric field at least partially cancelselectro-tonic currents in at least the portion of the heart chamber.

[0116] There is further provided, in accordance with a preferredembodiment of the invention a method of modifying a force of contractionof at least a portion of a heart chamber, comprising:

[0117] providing a subject having a heart, comprising at least a portionhaving an activation;

[0118] applying a non-excitatory electric field having a given duration,at a delay after the activation, to the portion between two positions;and

[0119] sensing an activation at a site between the two positions.

[0120] There is further provided, in accordance with a preferredembodiment of the invention a method of modifying a force of contractionof at least a portion of a heart chamber, comprising:

[0121] providing a subject having a heart, comprising at least a portionhaving an activation;

[0122] applying a non-excitatory electric field having a given duration,at a delay after the activation, to the portion between two positions;and

[0123] sensing an activation at a site coinciding with one of the twopositions.

[0124] There is further provided, in accordance with a preferredembodiment of the invention a method of modifying a force of contractionof at least a portion of a heart chamber, comprising:

[0125] providing a subject having a heart, comprising at least a portionhaving an activation;

[0126] applying a non-excitatory electric field having a given duration,at a delay after the activation, to the portion between two positions;

[0127] sensing an activation at a site; and

[0128] estimating the activation of the portion from the sensedactivation.

[0129] Preferably sensing comprises sensing a value of a parameter of anECG and wherein estimating comprises estimating the delay based on adelay value associated with the value of the parameter.

[0130] Preferably, the site is at a different chamber of the heart thanthe chamber at which the field is applied.

[0131] Preferably, the site is substantially the earliest activated sitein the chamber of the portion.

[0132] There is further provided, in accordance with a preferredembodiment of the invention a method of modifying a force of contractionof at least a portion of a heart chamber, comprising:

[0133] providing a subject having a heart, comprising at least a portionhaving an activation;

[0134] applying a non-excitatory electric field having a given duration,at a delay after the activation, to the portion; and

[0135] applying a second non-excitatory electric field to a secondportion of the chamber.

[0136] There is further provided, in accordance with a preferredembodiment of the invention a method according to claim 36, wherein thesecond field is applied in the same cardiac cycle as the non-excitatoryfield.

[0137] Preferably, each portion has an individual activation to whichthe applications of the field thereat are synchronized.

[0138] Preferably, the second field has a different effect on the heartthan the non-excitatory field.

[0139] Preferably, only the second non-excitatory field is appliedduring a different cardiac cycle.

[0140] There is further provided, in accordance with a preferredembodiment of the invention a method of modifying a force of contractionof at least a portion of a heart chamber, comprising:

[0141] providing a subject having a heart, comprising at least a portionhaving an activation;

[0142] estimating the activation at the portion; and

[0143] applying a non-excitatory electric field having a given duration,at a delay after the estimated activation, to the portion.

[0144] There is further provided, in accordance with a preferredembodiment of the invention a method of modifying a force of contractionof at least a portion of a heart chamber, comprising:

[0145] providing a subject having a heart, comprising at least a portionhaving an activation;

[0146] applying a non-excitatory electric field having a given duration,at a delay after the activation, to the portion; and

[0147] repeating application of the non-excitatory field, during aplurality of later heart beats, at least some of which are notconsecutive.

[0148] Preferably, the method comprises gradually reducing the frequencyat which beats are skipped during the repeated application.

[0149] There is further provided, in accordance with a preferredembodiment of the invention a method of modifying a force of contractionof at least a portion of a heart chamber, comprising:

[0150] providing a subject having a hearts comprising at least a portionhaving an activation;

[0151] applying a non-excitatory electric field having a given duration,at a delay after the activation, to the portion, wherein the portion hasan extent; and

[0152] changing the extent of the portion to which the field is applied,between beats.

[0153] There is further provided, in accordance with a preferredembodiment of the invention a method of modifying a force of contractionof at least a portion of a heart chamber, comprising:

[0154] providing a subject having a heart, comprising at least a portionhaving an activation;

[0155] irradiating the portion with light synched to the activation; and

[0156] repeating irradiating at at least 100 cardiac cycles, during aperiod of less than 1000 cardiac cycles.

[0157] There is further provided, in accordance with a preferredembodiment of the invention a method of modifying a force of contractionof at least a portion of a heart chamber, comprising:

[0158] providing a subject having a heart, comprising at least a portionhaving an activation;

[0159] irradiating the portion with radio frequency radiation synched tothe activation; and

[0160] repeating irradiating at at least 100 cardiac cycles, during aperiod of less than 1000 cardiac cycles.

[0161] There is further provided, in accordance with a preferredembodiment of the invention a method of modifying a force of contractionof at least a portion of a heart chamber, comprising:

[0162] providing a subject having a heart, comprising at least a portionhaving an activation; and

[0163] modifying the availability of calcium ions inside muscle fibersof the portion, during a period of time including a time less than 70msec after the activation, in response to the activation.

[0164] There is further provided, in accordance with a preferredembodiment of the invention a method of modifying a force of contractionof at least a portion of a heart chamber, comprising:

[0165] providing a subject having a heart, comprising at least a portionhaving an activation; and

[0166] modifying the transport rate of calcium ions inside muscle fibersof the portion, during a period of time less than 70 msec after theactivation, in response to the activation.

[0167] There is fierier provided, in accordance with a preferredembodiment of the invention a method of modifying a force of contractionof at least a portion of a heart chamber, comprising:

[0168] providing a subject having a heart, comprising at least a portionhaving an activation; and

[0169] modifying the availability of catecholamines at the portion insynchrony with the activation.

[0170] There is further provided, in accordance with a preferredembodiment of the invention a method of modifying the activation profileof at least a portion of a heart, comprising,

[0171] mapping the activation profile of the portion;

[0172] determining a desired change in the activation profile; and

[0173] modifying, using a non-excitatory electric field, the conductionvelocity in a non-arrhythmic segment of the portion, to achieve thedesired change.

[0174] In a preferred embodiment of the invention, wherein the desiredchange is an AV interval and wherein modifying comprises modifying theconduction velocities of purkinje fibers between an AV node and at leastone of the ventricles in the heart.

[0175] In a preferred embodiment of the invention, the activationcomprises an average activation of the portion.

[0176] In a preferred embodiment of the invention, the activationcomprises an earliest activation.

[0177] In a preferred embodiment of the invention, the activationcomprises a mechanical activation.

[0178] In a preferred embodiment of the invention, wherein theactivation comprises an electrical activation.

[0179] In a preferred embodiment of the invention, wherein the portioncomprises a plurality of subportions, each having an individualactivation and wherein applying a field comprises applying a field toeach subportion at a delay relative to the individual activation of thesubportion.

[0180] In a preferred embodiment of the invention, applying anon-excitatory electric field comprises driving an electric currentthrough the segment. Preferably, the current is less than 20 mA. in someembodiments of the invention the current is less than 8 mA, 5 mA, 3 mA.Preferably, the current is at least 0.5 mA. In some embodiments it is atleast 1 or 3 mA.

[0181] In a preferred embodiment of the invention, the field is appliedfor a duration of between 10 and 140 msec. In other preferredembodiments it is applied for between 20 and 100 msec, or 60 and 90msec.

[0182] In a preferred embodiment of the invention, the delay is lessthan 70 msec. In other preferred embodiments it is less than 40, 20, 5or 1 msec. In some embodiments the delay is substantially equal to zero.

[0183] In a preferred embodiment of the invention, the delay is at least1 msec. In other preferred embodiments it may be more than 3, 7, 15 or30 msec.

[0184] In a preferred embodiment of the invention, the electric fieldhas an exponential temporal envelope. In others it has a square,triangular, ramped or biphasic temporal envelope. Preferably theelectric field comprises an AC electric field, preferably having asinusoidal, saw tooth or square wave temporal envelope.

[0185] In a preferred embodiment of the invention, wherein the portionof the chamber has an inside surface and an outside surface, wherein thefield is applied along the inner surface.

[0186] In a preferred embodiment of the invention, wherein the portionof the chamber has a normal conduction direction, wherein the field isapplied along the normal conduction direction.

[0187] In a preferred embodiment of the invention, wherein the portionof the chamber has a normal conduction direction, wherein the field isapplied perpendicular to the normal conduction direction.

[0188] In a preferred embodiment of the invention, the field is appliedbetween at least two electrodes. Preferably, the electrodes are at least2 cm apart. In some preferred embodiments the electrodes are at least 4or 9 cm apart.

[0189] The chamber may be any of the left ventricle, the left atrium,the right ventricle or the right atrium.

[0190] A preferred embodiment of the invention includes pacing theheart. Preferably, applying the electric field is synchronized with thepacing. in a preferred embodiment of the invention, the method includescalculating the delay based on the pacing.

[0191] In a preferred embodiment of the invention, the method includessensing a specific activation at a site.

[0192] There is further provided, in accordance with a preferredembodiment of the invention, a method of modifying the activationprofile of at least a portion of a heart, comprising,

[0193] mapping the activation profile of the portion;

[0194] determining a desired change in the activation profile; and

[0195] blocking the activation of at least a segment of the portion, toachieve the desired change, wherein the segment is not part of a reentrycircuit an arrhythmia foci in the heart.

[0196] In a preferred embodiment of the invention, the blocked segmentis an ischemic segment.

[0197] There is further provides in accordance with a preferredembodiment of the invention a method of modifying the activation profileof at least a portion of a heart, comprising,

[0198] mapping the activation profile of the portion;

[0199] determining a desired change in the activation profile; and

[0200] changing the refractory period of at least a segment of theportion, to achieve the desired change, wherein the segment is not partof a reentry circuit or an arrhythmia a foci in the heart.

[0201] There is further provided, in accordance with a preferredembodiment of the invention a method of modifying the heart rate of aheart, comprising:

[0202] providing a subject having a heart with an active naturalpacemaker region; and

[0203] applying a non-excitatory electric field to the region.

[0204] Preferably, the electric field extends a duration of an actionpotential of the region.

[0205] Preferably the method comprises extending the refractory periodof a significant portion of the right atrium.

[0206] There is further provided, in accordance with a preferredembodiment of the invention a method of reducing an output of a chamberof a heart, comprising:

[0207] determining the earliest activation of at least a portion of thechamber, which portion is not part of an abnormal conduction pathway inthe heart; and

[0208] applying a non-excitatory electric field to the portion.

[0209] Preferably, the field is applied prior to activation of theportion.

[0210] Preferably, the field reduces the reactivity of the portion to anactivation signal.

[0211] Preferably, the field reduces the sensitivity of the portion toan activation signal.

[0212] There is further provided, in accordance with a preferredembodiment of the invention a method of reducing an output of a chamberof a heart, comprising:

[0213] determining an activation of and conduction pathways to at leasta portion of the chamber; and

[0214] reversibly blocking the conduction pathways, using a locallyapplied non-excitatory electric field.

[0215] There is further provided, in accordance with a preferredembodiment of the invention a method of reducing an output of a chamberof a heart, comprising:

[0216] determining an activation of and a conduction pathway to at leasta portion of the chamber, which portion is not part of an abnormalconduction pathway in the heart; and

[0217] reversibly reducing the conduction velocity in the conductionpathway, using a locally applied electric field.

[0218] There is fierier provided, in accordance with a preferredembodiment of the invention a method of performing cardiac surgery,comprising:

[0219] blocking the electrical activity to at least a portion of theheart using a non-excitatory electric field; and

[0220] performing a surgical procedure on the portion.

[0221] There is further provided, in accordance with a preferredembodiment of the invention a method of performing cardiac surgery,comprising:

[0222] reducing the sensitivity to an activation signal of at least aportion of the heart using a non-excitatory electric field; and

[0223] performing a surgical procedure on the portion.

[0224] There is further provided, in accordance with a preferredembodiment of the invention a method of controlling the heart,comprising,

[0225] providing a subject having a heart with a left ventricle and aright ventricle;

[0226] selectively reversibly increasing the contractility of one of theventricles relative to the other ventricle.

[0227] Preferably, selectively reversibly increasing comprises applyinga non-excitatory electric field to at least a portion of the oneventricle.

[0228] There is further provided, in accordance with a preferredembodiment of the invention a method of controlling the heart,comprising,

[0229] providing a subject having a heart with a left ventricle and aright ventricle;

[0230] selectively reversibly reducing the contractility of one of theventricles, relative to the other ventricle.

[0231] Preferably, selectively reversibly reducing comprises applying anon-excitatory electric field to at least a portion of the oneventricle.

[0232] There is further provided, in accordance with a preferredembodiment of the invention a method of treating a segment of a heartwhich is induces arrhythmias due to an abnormally low excitationthreshold, comprising:

[0233] identifying the segment; and

[0234] applying a desensitizing electric field to the segment, such thatthe excitation threshold is increased to a normal range of values.

[0235] There is further provided, in accordance with a preferredembodiment of the invention a method of modifying an activation profileof at least a portion of a heart, comprising:

[0236] determining a desired change in the activation profile; and

[0237] reversibly blocking the conduction of activation signals across aplurality of elongated fence portions of the heart to achieve thedesired change.

[0238] Preferably, blocking the conduction creates a plurality ofsegments, isolated from external activation, in the portion of theheart. Preferably, at least one of the isolated segments contains anarrhythmia foci. Preferably, at least one of the isolated segments doesnot contain an arrhythmia foci.

[0239] Preferably, the method includes individually pacing each of atleast two of the plurality of isolated segments.

[0240] Preferably, blocking the conduction limits an activation frontfrom traveling along abnormal pathways.

[0241] Preferably, reversibly blocking comprises reversibly blockingconduction of activation signals, synchronized with a cardiac cycle, toblock abnormal activation signals.

[0242] In a preferred embodiment of the invention reversibly blockingcomprises reversibly blocking conduction of activation signals,synchronized with a cardiac cycle, to pass normal activation signals.

[0243] There is further provided, in accordance with a preferredembodiment of the invention a method of treating abnormal activation ofthe heart, comprising:

[0244] detecting an abnormal activation state; and

[0245] modifying the activation of the heart in accordance with theabove described method to stop the abnormal activation condition.

[0246] In a preferred embodiment of the invention the abnormal conditionis fibrillation.

[0247] There is further provided in accordance with a preferredembodiment of the invention a method of controlling the heartcomprising:

[0248] determining a desired range of values for at least one parameterof cardiac activity; and

[0249] controlling at least a local force of contraction in the heart tomaintain the parameter within the desired range.

[0250] Preferably, controlling includes controlling the heart rate.

[0251] Preferably, controlling includes controlling a local conductionvelocity.

[0252] Preferably, the parameter responds to the control with a timeconstant of less than 10 minutes. Alternatively it responds with a timeconstant of more than a day.

[0253] There is further provided, in accordance with a preferredembodiment of the invention a method of controlling the heart,comprising:

[0254] determining a desired range of values for at least one parameterof cardiac activity;

[0255] controlling at least a portion of the heart using anon-excitatory electric field having at least one characteristic, tomaintain the parameter within the desired range; and

[0256] changing the at least one characteristic in response to areduction in a reaction of the heart to the electric field.

[0257] Preferably, the characteristic is a strength of the electricfield. Alternatively it comprises a duration of the electric field, afrequency of the field or a wave form of the field.

[0258] There is further provided, in accordance with a preferredembodiment of the invention a method of treating a patient having aheart with an unhealed infarct, comprising, applying any of the abovemethods, until the infarct is healed.

[0259] There is further provided, in accordance with a preferredembodiment of the invention a method of treating a patient having aheart, comprising, providing a patient, having an unhealed infarct inthe heart; and

[0260] applying one of the above methods until the heart is stabilized.

[0261] In a preferred embodiment of the invention applying anon-excitatory field comprises applying a non-excitatory field forbetween 3 and 5000 heart beats.

[0262] There is further provided, in accordance with a preferredembodiment of the invention apparatus for controlling a heartcomprising:

[0263] a plurality of electrodes adapted to apply an electric fieldacross at least a portion of the heart; and

[0264] a power supply which electrifies the electrodes with anon-excitatory electric field, for a given duration at least 100 timesduring a period of less than 50,000 cardiac cycles.

[0265] Preferably, are electrified at least 1000 times during a periodof less than 50,000 cardiac cycles. They may also be electrified atleast 1000 times during a period of less than 20,000 cardiac cycles orat least 1000 times during a period of less than 5,000 cardiac cycles.

[0266] Preferably, the field is applied less than 10 times in onesecond.

[0267] In a preferred embodiment of the invention, the power supplyelectrifies the electrodes at least 2000 times over the period. Inpreferred embodiments the power supply electrifies the electrodes atleast 4000 times over the period.

[0268] There is further provided in accordance with a preferredembodiment of the invention apparatus for controlling a heartcomprising:

[0269] a plurality of electrodes adapted to apply an electric fieldacross at least a portion of the heart; and

[0270] a power supply which electrifies the electrodes with anon-excitatory electric field, for a given duration,

[0271] wherein at least one of the electrodes is adapted to cover anarea of the heart larger than 2 cm².

[0272] Preferably at least one of the electrodes is adapted to cover anarea of the heart larger than 6 or 9 cm².

[0273] There is further provided, in accordance with a preferredembodiment of the invention apparatus for controlling a heartcomprising:

[0274] at least one unipolar electrode adapted to apply an electricfield to at least a portion of the heart; and

[0275] a power supply which electrifies the electrodes with anon-excitatory electric fields.

[0276] Preferably the apparatus comprises a housing, which iselectrified as a second electrode.

[0277] There is further provided, in accordance with a preferredembodiment of the invention apparatus for controlling a heartcomprising:

[0278] a plurality of electrodes adapted to apply an electric fieldacross at least a portion of the heart; and

[0279] a power supply which electrifies the electrodes with anon-excitatory electric field, for a given duration,

[0280] wherein the distance between the electrodes is at least 2 cm.

[0281] In preferred embodiments of the invention the distance is atleast 4 or 9 cm.

[0282] There is further provided, in accordance with a preferredembodiment of the invention apparatus for controlling a heartcomprising:

[0283] at least three electrodes adapted to apply an electric fieldacross at least a portion of the heart; and

[0284] a power supply which electrifies the electrodes with anon-excitatory electric field, for a given duration,

[0285] wherein the electrodes are selectively electrifiable in at leasta first configuration where two electrodes are electrified and in asecond configuration where two electrodes, not both identical with thefirst configuration electrodes, are electrified.

[0286] There is further provided, in accordance with a preferredembodiment of the invention apparatus for controlling a heartcomprising:

[0287] a plurality of electrodes adapted to apply an electric fieldacross at least a portion of the heart;

[0288] a sensor which senses a local activation; and

[0289] a power supply which electrifies the electrodes with anon-excitatory electric field, for a given duration, responsive to thesensed local activation.

[0290] Preferably the sensor senses a mechanical activity of theportion.

[0291] Preferably, the sensor is adapted to sense the activation at atleast one of the electrodes.

[0292] Preferably, the sensor is adapted to sense the activation in theright atrium.

[0293] Preferably, the sensor is adapted to sense the activation betweenthe electrodes.

[0294] Preferably, the sensor senses an earliest activation in a chamberof the heart including the portion and wherein the power supply timesthe electrification responsive to the earliest activation.

[0295] There is further provided, in accordance with a preferredembodiment of the invention apparatus for controlling a heartcomprising:

[0296] electrodes adapted to apply an electric field across elongatesegments of at least a portion of the heart; and

[0297] a power supply which electrifies the electrodes with a nonexcitatory electric field.

[0298] Preferably, the electrodes are elongate electrodes at least onecm long. In other embodiments they are at least 2 or 4 cm long.Preferably the segments are less than 0.3 cm wide. In some embodimentsthey are less than 0.5, 1 or 2 cm wide.

[0299] Preferably, the power supply electrifies the electrodes for agiven duration of at least 20 msec, at least 1000 times over a period ofless than 5000 cardiac cycles.

[0300] In preferred embodiments of the invention, the elongate segmentsdivide the heart into at least two electrically isolated segments in theheart.

[0301] There is further provided, in accordance with a preferredembodiment of the invention apparatus for controlling a heartcomprising:

[0302] a plurality of electrodes adapted to apply an electric fieldacross at least a portion of the heart;

[0303] a power-supply which electrifies the electrodes with anon-excitatory electric field, for a given duration; and

[0304] a circuit for determining an activation at a site in the portion,

[0305] wherein the power supply electrifies the electrodes responsive tothe determined activation.

[0306] Preferably, the electric field is applied at a given delay,preferably less than 70 msec, after an activation at one of theelectrodes.

[0307] In a preferred embodiment of the invention the electric field isapplied before an activation at one of the electrodes. In variouspreferred embodiments of the invention the field is applied more than30, 50 or 80 msec before the activation.

[0308] Preferably, the circuit comprises an activation sensor whichsenses the activation. Alternatively or additionally the activation iscalculated, preferably based on an activation in a chamber of the heartdifferent from a chamber including the portion.

[0309] Preferably the apparatus includes a memory which stores valuesused to calculate a delay time, associated with a value of at least aparameter of a sensed ECG. Preferably, the parameter is a heart rate.

[0310] There is further provided, in accordance with a preferredembodiment of the invention apparatus for controlling a heartcomprising:

[0311] a plurality of electrodes adapted to apply an electric fieldacross at least a portion of the heart;

[0312] a power supply which electrifies the electrodes with anon-excitatory electric field, for a given duration;

[0313] a sensor which measures a parameter of cardiac activity, and acontroller which controls the electrification of the electrodes tomaintain the parameter within a range of values.

[0314] The apparatus preferably comprises a memory which stores a map ofelectrical activity in the heart, wherein the controller uses the map todetermine a desired electrification.

[0315] The apparatus preferably comprises a memory which stores a modelof electrical activity in the heart, wherein the controller uses themodel to determine a desired electrification.

[0316] There is further provided, in accordance with a preferredembodiment of the invention apparatus for controlling a heartcomprising:

[0317] a plurality of electrodes adapted to apply an electric fieldacross at least a portion of the heart;

[0318] a power supply which electrifies the electrodes with anon-excitatory electric field, for a given duration; and

[0319] a controller which measures a reaction of the heart to theelectrification of the electrodes.

[0320] Preferably, the controller changes the electrification based onthe measured reaction.

[0321] Preferably, the apparatus includes a memory which stores themeasured reaction.

[0322] There is further provided, in accordance with a preferredembodiment of the invention apparatus for controlling a heartcomprising:

[0323] a plurality of electrodes adapted to apply an electric fieldacross at least a portion of the heart;

[0324] a power supply which electrifies the electrodes with anon-excitatory electric field, for a given duration; and

[0325] a pacemaker which paces the heart.

[0326] Preferably, the pacemaker and the remainder of the apparatus arecontained in a common housing.

[0327] Preferably, the pacemaker and the remainder of the apparatusutilize common excitation electrodes. Preferably, the pacemaker and theremainder of the apparatus utilize a common power supply.

[0328] Preferably, the non-excitatory field is synchronized to thepacemaker.

[0329] Preferably, the electrodes are electrified using a single pulsewhich combines a pacing electric field and a non-excitatory electricfield.

[0330] There is further provided, in accordance with a preferredembodiment of the invention apparatus for controlling a heartcomprising:

[0331] a plurality of electrodes adapted to apply an electric fieldacross at least a portion of the heart; and

[0332] a power supply which electrifies the electrodes with anon-excitatory electric field, for a given duration,

[0333] wherein at least one of the electrodes is mounted on a catheter.

[0334] There is further provided, in accordance with a preferredembodiment of the invention apparatus for controlling a heartcomprising:

[0335] a plurality of electrodes adapted to apply an electric fieldacross at least a portion of the heart; and

[0336] a power supply which electrifies the electrodes with anon-excitatory electric field, for a given duration,

[0337] wherein the electrodes are adapted to be applied externally tothe body.

[0338] Preferably, the apparatus includes an external pacemaker.

[0339] Preferably, the apparatus comprises an ECG sensor, to whichelectrification of the electrodes is synchronized.

[0340] In a preferred embodiment of the invention the duration of thefield is at least 20 msec. In other preferred embodiments the durationis at least 40, 80 or 120.

[0341] In a preferred embodiment of the invention a current is forcedthrough the portion. between the electrodes.

[0342] Preferably, the apparatus includes at least another twoelectrodes, electrified by the power supply and adapted to apply anon-excitatory electric field across a second portion of the heart.Preferably, the apparatus comprises a controller which coordinates theelectrification of all the electrodes in the apparatus.

[0343] Preferably, a peak current through the electrodes is less than 20mA. In some preferred embodiments it is less than 10, 5 or 2 mA.

[0344] In preferred embodiments of the invention the electrodes areadapted to be substantially in contact with the heart.

[0345] Preferably the electric field has an exponential, triangular orsquare wave shape. The field may be unipolar or bipolar. The field mayhave a constant strength.

[0346] There is further provided, in accordance with a preferredembodiment of the invention apparatus for optical control of a heart,comprising:

[0347] at least one implantable light source which generates pulses oflight, for at least 1000 cardiac cycles, over a period of less than 5000cycles; and

[0348] at least one wave guide for providing non-damaging intensities oflight from the light source to at least one site on the heart.

[0349] Preferably, the at least one light source comprises a pluralityof light sources, each attached to a different site on the heart.

[0350] Preferably, the wave guide is an optical fiber.

[0351] Preferably, the light source comprises a monochrome light source.

[0352] In a preferred embodiment of the invention the apparatuscomprises a sensor, which measures an activation of at least portion ofthe heart, wherein the light source provides pulsed light in synchronywith the measured activation.

[0353] There is further provided, in accordance with a preferredembodiment of the invention a method of programming a programmablecontroller for a subject having a heart, comprising:

[0354] determining pulse parameters suitable for controlling the heartusing non-excitatory electric fields; and

[0355] programming the controller with the pulse parameters.

[0356] Preferably, determining pulse parameters comprises determining atiming of the pulse relative to a cardiac activity.

[0357] Preferably, the cardiac activity is a local.

[0358] Preferably, determining a timing comprises determining timingwhich does not induce fibrillation in the heart.

[0359] Preferably, determining a timing comprises determining a timingwhich does not induce an arrhythmia in the heart.

[0360] Preferably, determining a timing comprises determining the timingbased on a map of an activation profile of the heart.

[0361] Preferably, determining a timing comprises calculating a delaytime relative to a sensed activation.

[0362] Preferably, controlling the heart comprises modifying thecontractility of the heart There is further provided, in accordance witha preferred embodiment of the invention a method of determining anoptimal placement of at least two individual electrodes for controllinga heart using non-excitatory electric fields, comprising:

[0363] determining an activation profile of at least a portion of theheart; and

[0364] determining an optimal placement of the electrodes in the portionbased on the activation profile.

[0365] Preferably the method includes determining an optimal locationfor an activation sensor, relative to the placement of the electrodes.

[0366] Preferably, controlling comprises modifying the contractility.

[0367] Preferably, controlling comprises creating elongatenon-conducting segments in the heart.

[0368] There is further provided, in accordance with a preferredembodiment of the invention a method of determining a timing parameterfor a non-excitatory, repeatably applied pulse for a heart, comprising:

[0369] applying a non-excitatory pulse using a first delay;

[0370] determining if the pulse induces an abnormal activation profilein the heart; and

[0371] repeating applying a non-excitatory pulse using a second delay,shorter than the first, if the pulse did not induce abnormal activationin the heart.

[0372] There is further provided, in accordance with a preferredembodiment of the invention a method of determining a timing parameterfor a non-excitatory, repeatably applied pulse for a heart, comprising:

[0373] applying a non-excitatory pulse using a first delay;

[0374] determining if the pulse induces an abnormal activation profilein the heart; and

[0375] repeating applying a non-excitatory pulse using a second delay,longer than the first, if the pulse did not induce abnormal activationin the heart.

[0376] There is further provided, in accordance with a preferredembodiment of the invention a method of programming a programmablecontroller for a heart, comprising:

[0377] controlling the heart using plurality of non-excitatory electricfield sequences;

[0378] determining a response of the heart to each of the sequences; and

[0379] programming the controller responsive to the response of theheart to the non-excitatory sequences.

[0380] There is further provided, in accordance with a preferredembodiment of the invention a method of controlling an epilepticseizure, comprising:

[0381] detecting an epileptic seizure in brain tissue; and

[0382] applying a non-excitatory electric field to the brain tissue toattenuate conduction of a signal in the tissue.

[0383] There is further provided, in accordance with a preferredembodiment of the invention a method of controlling nervous signals inperiphery nerves, comprising,

[0384] selecting a nerve; and

[0385] applying a non-excitatory electric field to the nerve toattenuate conduction of nervous signals in the nerve.

[0386] There is further provided, in accordance with a preferredembodiment of the invention a method of controlling a heart having achamber comprising:

[0387] applying a non-excitatory electric field to a first portion of achamber, such that a force of contraction of the first portion islessened; and

[0388] applying a non-excitatory electric field to a second portion of achamber, such that a force of contraction of the second portion isincreased. heart beat. Alternatively or additionally, the delay is atleast 0.5 or 1 msec, optionally, 3 msec, optionally 7 msec and alsooptionally 30 msec.

[0389] There is further provided in accordance with a preferredembodiment of the invention, a method of controlling the heart includingdetermining a desired range of values for at least one parameter ofcardiac activity and controlling at least a local contractility and alocal conduction velocity in the heart to maintain the parameter withinthe desired range.

[0390] Preferably, the parameter responds to the control with a timeconstant of less than 10 minutes, alternatively, the parameter respondsto the control with a time constant of between 10 minutes and 6 hours,alternatively, with a time constant of between 6 hours and a day,alternatively, with a time constant between a day and a week,alternatively, a time constant of between a week and month,alternatively, a time constant of over a month.

[0391] There is also provided in accordance with a preferred embodimentof the invention, a method of controlling the heart, includingdetermining a desired range of values for at least one parameter ofcardiac activity, controlling at least a portion of the heart using anon-excitatory electric field having at least one characteristic, tomaintain the parameter within the desired range and changing the atleast one characteristic in response to a reduction in a reaction of theheart to the electric field. Preferably, the characteristic is thestrength of the electric field. Alternatively or additionally, thecharacteristic is one or more of the duration of the electric field, itstiming, wave form, and frequency.

[0392] In another preferred embodiment of the invention, the apparatusincludes a sensor which measures a parameter of cardiac activity and acontroller which controls the electrification of the electrodes tomaintain the parameter within a range of values. Preferably, theapparatus includes a memory which stores a map of electrical activity inthe heart, wherein the controller uses the map to determine a desiredelectrification. Alternatively or additionally, the apparatus includes amemory which stores a model of electrical activity in the heart, whereinthe controller uses the model to determine a desired electrification.

[0393] There is also provided in accordance with a preferred embodimentof the invention, a method of controlling an epileptic seizure,including detecting an epileptic seizure in brain tissue and applying anon-excitatory electric field to the brain tissue to attenuateconduction of a signal in the tissue.

BRIEF DESCRIPTION OF THE DRAWINGS

[0394] The present invention will be more clearly understood from thedetailed description of the preferred embodiments and from the attacheddrawings-in which:

[0395]FIG. 1A is a schematic graph of a typical cardiac muscle actionpotential;

[0396]FIG. 1B is a schematic model of a cardiac muscle cell in anelectrical field;

[0397]FIG. 2 is a schematic diagram of a heart having segmentscontrolled in accordance with embodiments of the present invention;

[0398]FIG. 3 is a schematic diagram of a segment of right atrial tissuewith a plurality of conduction pathways, illustrating the use of fences,in accordance with a preferred embodiment of the present invention;

[0399]FIG. 4A is a schematic diagram of an electrical controllerconnected to a segment of cardiac muscle, in accordance with a preferredembodiment of the invention;

[0400]FIG. 4B is a schematic diagram of an electrical controllerconnected to a segment of cardiac muscle, in accordance with a preferredembodiment of the invention;

[0401]FIG. 5 is a schematic diagram of an experimental setup used fortesting the feasibility of some embodiments of the present invention;

[0402] FIGS. 6A-6C are graphs showing the results of variousexperiments;

[0403]FIG. 7A is a graph summarizing results of experimentation on anisolated segment of cardiac muscle fibers, and showing the effect of adelay in applying a pulse in accordance with an embodiment of theinvention, on the increase in contractile force;

[0404]FIG. 7B is a graph summarizing results of experimentation on anisolated segment of cardiac muscle fibers, and showing the effect of aduration of the pulse on the increase in contractile force;

[0405]FIG. 7C is a graph summarizing results of experimentation on anisolated segment of cardiac muscle fibers, and showing the effect of acurrent intensity of the pulse on the increase in contractile force;

[0406]FIG. 8A is a graph showing the effect of a controlling current ona heart rate, in accordance with a preferred embodiment of theinvention;

[0407]FIG. 8B is a series of graphs showing the repeatability ofincreasing contractility in various types of cardiac muscles, inaccordance with a preferred embodiment of the invention;

[0408] FIGS. 9-18B are each a series of graphs showing experimentalresults from experiments in which an isolated rabbit heart wascontrolled in accordance with an embodiment of the present invention;and

[0409] FIGS. 19-23 are each a series of graphs showing experimentalresults from experiments in which an in-vivo rabbit heart was controlledin accordance with an embodiment of the present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0410] One aspect of the present invention relates to controlling and/ormodulating the contractility of a cardiac muscle segment and/or theplateau duration of an action potential of the cardiac muscle segment,by applying an electric field or current across the segment. As usedherein, the terms, voltage, electric field and current are usedinterchangeably to refer to the act of supplying a non-excitatory signalto control cardiac activity. The actual method of applying the signal isdescribed in more detail below.

[0411]FIG. 1B shows a schematic model illustrating one possibleexplanation for the relation between an applied voltage and a resultingplateau duration. A cell 20, having a membrane 26, surrounded byextra-cellular fluid 28, is located in an electrical field generated byan electrode 22 and an electrode 24. Cell 20 has a −40 mV internalpotential across membrane 26, electrode 22 has a potential of 40 mV andelectrode 24 is grounded (to the rest of the body). During the actionpotential plateau, calcium ions enter the cell and potassium ions leavethe cell trough different membrane proteins. In this model, the externalelectric field caused by the voltage on the electrodes increases thepotential of extra-cellular fluid 28. This reduces the outward movementof potassium ions from inside cell 20 and/or forces calcium ions intocell 20, either by changing the membrane potential, thus changing theelectrochemical driving force of ions from both sides of the membrane orby changing the number of ionic channels being opened or closed.

[0412] In an additional or alternative model, the electric fieldgenerated by electrodes 22 and 24 causes an ionic flow between them.This flow is carried mainly by chlorine and potassium ions, since theseare the ions to which membrane 26 is permeable, however, calcium ionsmay also be affected. In this model, calcium ions are drawn into cell 20by the current while potassium ions are removed. Alternatively oradditionally, sodium ions are removed instead of potassium ions. In anycase, the additional calcium ions in the cell increase the contractilityof cell 20 and are believed to extend the plateau duration.

[0413] Another additional or alternative model is that the electricfield and/or the ionic current affect the opening and closing ofvoltage-gated charnels (sodium, potassium and sodium-calcium). Further,the field may affect the operation of ionic pumps. One possiblemechanism for this effect is that the applied electric field generateslocal “hot spots” of high electrical fields in the cell membrane, whichhot spots can affect the opening and closing of ionic channels and/orpumps. Since creation of the hot spots is generally asymmetric withrespect to the cell and since the channels themselves have an asymmetricbehavior with respect to applied fields, more channels may be opened atone end of the cell than at the other. If, for example, more channelsopen at the negative end of the cell than at the positive end of thecell, the inflow of calcium ions will be greater than the outflow ofthese ions.

[0414] In accordance with yet another model, the controlling electricfield increases the concentration of calcium in intracellular stores,which increased concentration may cause increased and/or faster supplyof calcium during contraction, increasing the contractile force.Alternatively or additionally, the controlling electric field maydirectly affect the rate at which calcium is made available from theintracellular store, during contraction of the cell. Also, it may bethat the controlling electric field directly increases the efficiency ofthe inflow of calcium, which causes an increase in the availability ofcalcium from the intracellular stores. It should be noted that in somephysiological models of myocyte contraction, it is the rate of calciumflow which determines the contractility, rather than the total amount ofcalcium.

[0415] Different types of ionic channels and pumps have differentoperating characteristics These characteristics include rates of flow,opening and closing rates, triggering voltage levels, priming anddependency on other ions for operating. It is thus possible to select aparticular type of ionic channel by applying a particular strength ofelectric field, which strength also depends on whether the channels areopen or closed at that moment, i.e., on thedepolarization/repolarization phase of the cell. Different attributes ofcellular activity may be controlled by controlling the ionic channels inthis manner, since the activity of excitable tissues are well determinedby their transmembrane potential and the concentrations of various typesof ions inside and outside the cell.

[0416] Another model is that applying a non-excitatory electric fieldsinduces the release of catecholamines (from nerve endings) at thetreated portion of the heart. Another possibility is that the appliedfield facilitates the absorption of existing catecholamines by the cell.

[0417] Another, “recruitment”, model, hypothesizes that thenon-excitatory pulse recruits cardiac muscle fibers which are otherwisenot stimulated by the activation signal. The non-excitatory pulse maywork by lowering their depolarization threshold or by supplying a higherstrength activation signal than is normal. However, it is generallyaccepted that cardiac muscle fibers function as a syncytium such thateach cell contracts at each beat. See for example, “ExcitationContraction Coupling and Cardiac Contractile Force”, by Donald M. Bers,Chapter 2, page 17, Kluwer Academic, 1991.

[0418] Most probably, one or more of these models may be used to explainthe activity of cell 20 during different parts of the activation cycle.However, several major effects, including, increasing contractility,changing the self-activation rate, rescheduling of the repolarization,extension of plateau duration, hyperpolarization of cells, changing ofmembrane potential, changing of conduction velocity and inactivation ofcells using electric fields, can be effected without knowing which modelif any, is correct.

[0419] As can be appreciated, the direction of the electric field may beimportant. First, conduction in cardiac cells is very anisotropic.Second, the distribution of local irregularities in the cell membrane isnot equal, rather, irregularities are more common at ends of the cell;in addition, one cell end is usually more irregular than the other cellend. These irregularities may govern the creation of local high electricfields which might affect ionic channels. Third, some cardiacstructures, such as papillary muscles, are better adapted to conduct anactivation signal in one direction than in an opposite direction.Fourth, there exist rhythmic depolarization signals originating in thenatural conductive system of the heart which are caused by thedepolarization and repolarization of the heart muscle tissue itself.These signals may interfere with an externally applied electric field.

[0420] In one preferred embodiment of the invention, the purpose of aparticular electric field is to induce an ionic current which isopposite to an ionic current induced by the voltage potential caused bythe rhythmic depolarization of the heart. For example, the actionpotential plateau duration in cardiac muscle cells further from theearliest activation location is typically shorter than the duration ofthose cells nearer the earliest activation location. This shortening mayresult from different local ionic currents caused by the depolarizationand repolarization of the heart and/or by different ionic currentkinetics behavior at these locations. These ionic currents can benegated by applying an electric field of an equal magnitude and oppositedirection to the field generated by the rhythmic depolarization.

[0421]FIG. 2 shows a heart 30 which is controlled using an electricalcontroller 32. A segment 38 of the right atrium is a controlled segment.In one preferred embodiment of the invention, the casing of controller32 is one electrode and an electrode 36 is a second electrode forapplying an electric field to segment 38. In another preferredembodiment of the invention, a second electrode 34 is used instead ofthe casing of controller 32. In a further preferred embodiment of theinvention, the body of controller 32 is a ground, so that both electrode34 and electrode 36 can be positive or negative relative to the rest ofthe heart. In another embodiment, electrode 34 is not directly connectedto heart 30, rather, electrode 34 is floating inside the heart. In thisembodiment, electrode 34 is preferably the current drain electrode. Forillustrative purposes, controller 32 is shown including a power supply31, leads 29A and 29B connecting the controller to the electrodes and amicroprocessor 33 which controls the electrification of the electrodes.

[0422] In an alternative embodiment, also shown in FIG. 2, the electricfield is applied along the heart wall, rather than across it. A segment35 of the left ventricle is shown to be controlled by two electrodes 37operated by a controller 39. Electrodes 37 may be placed on the surfaceof heart 30, alternatively, electrodes 37 may be inserted into the heartmuscle. Further alternatively, the electrodes may be placed in bloodvessels or in other body tissues which are outside of the heart,providing that electrifying the electrodes will provide a field orcurrent to at least a portion of the heart. It should be noted tat,since the control is synchronized to the cardiac cycle, even if theelectrodes are outside the heart, there is substantially no change inposition of the heart between sequential heart beats, so substantiallythe same portion of the heart will be affected each cardiac cycle, evenif the electrodes are not mechanically coupled to the heart.

[0423] It another alternative embodiment of the invention, more than onepair of electrodes is used to control segment 35. In such an embodiment,each pair of electrodes may be located differently with respect tosegment 35, for example, one pair of electrodes may be placed on theepicardium and a second pair placed inside the myocardium.

[0424] It should be appreciated that a current induced between theelectrodes may cause electrolytic deposition on the electrodes over aperiod of time and/or may cause adverse physiological reactions in thetissue. To counteract this effect, in a preferred embodiment of theinvention, the electric field is an AC electric field. In one preferredembodiment, the direction of the field is switched at a relatively lowfrequency, equal to or lower than the cardiac cycle rate. Preferably,the phase is inverted during a particular phase of the cardiac cycle,for example, during diastole. In another preferred embodiment of theinvention, the electric field has a frequency which is significantlyhigher than the cardiac cycle frequency.

[0425] Fast sodium channels, once inactivated require a certain amountof time at a negative potential to become ready for activation. Asdescribed, for example, in “Ionic Channels of Excitable Membranes”,Bertil Hille, chapter 2, pp. 40-45, Sinaur Associates Inc., thedisclosure of which is incorporated herein by reference. Since mostsodium cells are not activated immediately at the onset ofdepolarization, applying a voltage at a high enough frequency can openthe few channels that do react quickly to potential changes, while mostof the channels will become inactivated and will not leave theinactivation stage. Thus, if the frequency of the field is high enoughcertain ionic channels can be kept closed even though the averagevoltage is zero, with the result that the stimulated tissue isnon-excitatory.

[0426] In accordance with another preferred embodiment of the invention,an AC field is overlaid on a DC field for controlling the heart. Forexample, an AC field having a amplitude of 20% that of the DC field anda frequency of 1 kHz may be useful. Such an AC/DC controlling field hasthe advantage that the change in the applied field is higher, so thatany reactions (on the part of the muscle cell) to changes in the fieldare facilitated, as are any reactions to the intensity of the field. TheAC field in a combined AC/DC field or in a pure AC type field may have atemporal form of a sawtooth, a sinusoid or another form, such as anexponential or square wave pulls form.

[0427] In a DC type field, the temporal form of the field is preferablythat of a constant amplitude pulse. However, in other embodiment of theinvention, a triangular pulse, an exponential pulse, a ramp shaped pulse(in or decreasing), and/or a biphasic pulse form may be used.

[0428] Both AC and DC fields may be unipolar or bipolar. The terms ACand DC, as used herein to describe the electric field, relate to thenumber of cycles in a pulse. A DC filed has at most one cycle, while anAC field may comprise many cycles. In other preferred embodiments of theinvention, a train of pulses may be applied, each train being of an ACor of a DC type.

[0429] Various types of ionic electrodes, such as Ag—AgCl electrodes,platinum electrodes, titanium electrodes with coatings such as nitridesand carbides, coated tantalum electrodes, pyrocarbon electrodes orcarbon electrodes may be used. These electrodes generally reduce theamount of electro-deposition. The electrodes may be square, rectangular,or of any other suitable shape and may be attached by screwing theelectrode into the myocardium or by clamping or by other attachmentmethods.

[0430] There are two preferred methods of delivering an electric fieldto a segment of the heart. In a first method, a current is formedthrough the segment of the heart which is to be controlled. Preferably,the current is a constant DC current. However, an AC current, asdescribed above may also be used. In a second method, an electric fieldis applied across the heart (and maintained at a constant strengthrelative to the signal from). Generally, applying an electric field iseasier and requires less power than inducing a current.

[0431] The timing of the application of the electric field (or current)relative to the local activity at segment 38 and relative to the entirecardiac cycle is important. In general, the application of the field maybe synchronized to the local activation time if a local effect isdesired, such as increasing the local contractility and/or plateauduration. The application of the field may be synchronized to thecardiac cycle in cases where a global effect is desired. For example, byhyperpolarizing cells in synchrony with the cardiac cycle it is possibleto time their excitability window such that certain arrhythmias areprevented, as described in greater detail below. The application of thefield may also be synchronized in accordance with a model of how theheart should be activated, in order to change the activation profile ofthe heart. For example, to increase the output of the heart, conductionvelocities and/or conduction pathways may be controlled so that theheart contracts in a sequence deemed to be more optimal than a naturalsequence. In particular, by controlling the conduction velocity at theAV node and/or at the left and right branches the AV interval may beincreased or reduced. It should however be appreciated that thedifference in activation times between different parts of the heart,especially in the same chamber of the heart, is usually quite small. Forexample, the propagation time of an activation signal in the leftventricle is approximately between 15 and 50 msec. If the controlfunction may be achieved even if the timing of the application of thecontrolling field is locally off by 5 or 10 msec, then the controlfunction can be achieved using a single pair of controlling electrodes.

[0432] Although, it is usually simplest to determine the localactivation using a measured electrical activation time, it should beappreciated that the local activation of a tissue segment may bedetermined based on changes in mechanical activity, changes in position,velocity of motion, acceleration and even transmembrane potentials.Further, since in diseased tissue the delay between electricalactivation and mechanical activation may be longer than in healthytissue, the timing of the application of the field is preferablyrelative to the mechanical activation of the muscle.

[0433] In a prefer embodiment of the invention, the timing of the fieldis relative to the actual transmembrane potentials in the segments, notthose which may be estimated from the electrogram and/or the mechanical.Thus, initiation of the field may be timed to the onset of the plateauto increase contractility. Alternatively, application of the field maybe timed to specific transmembrane voltage levels. Further preferably,the strength and/or other parameters of the field, may be determinedresponsive to the actual transmembrane potentials and ionicconcentrations achieved in cells of the segment. One way of determiningthe actual voltage levels is to inject a voltage sensitive dye into thecell and monitor it using an optical sensor, such as known in the art inexperimental settings. One way of monitoring ionic concentrations, bothintracellular and extracellular is by using concentration sensitivedyes.

[0434] If an electric field is applied before the activation signalreaches segment 38, the electric field can be used to reduce thesensitivity of segment 38 to the activation signal. One method ofproducing this effect is to apply a large electric field opposite to thedirection of the activation signal and synchronized to it. This fieldwill reduce the amplitude of the activation signal, so that it cannotexcite cardiac tissue. Another method is to apply a strong positivepotential on segment 38 before an activation signal reaches it, so thatsegment 38 is hyperpolarized and not sensitive to the activation signal.Removing the electric field does not immediately reverse this effect.Segment 38 stays insensitive for a short period of time and for afurther period of time, the conduction velocity in segment 38 isreduced. In some cases however, removing the electric field will causean action potential to occur. This action potential can be timed so thatit occurs during a safe period with respect to the activation profile ofthe hear; so that if the segment generates an activation signal, thissignal will not be propagated to other parts of the heart. In somecases, the application of the field may affect the reactivity of thecells to the electrical potential rather and, in others, it may extendthe refractory period. It should be noted that an electric field appliedshortly after activation may also extend the refractory period, inaddition to increasing the force of contraction.

[0435] It should be noted that, since the cardiac cycle is substantiallyreported, a delay before the activation time and a delay after theactivation time may both be embodied using a system which delays afterthe activation time. For example, a field which should be applied 20msec before the activation time, may be applied instead 680 msec after(assuming the cycle length is 700 msec).

[0436] Other applications of electric fields can increase the conductionvelocity, especially where the conduction velocity is low as a result oftissue damage. Another method of controlling conduction is to apply anelectric field similar to that used for defibrillation. When appliedduring the repolarization period of these cells, this type of electricfield delays the repolarization. During this delayed/extendedrepolarization the cells are non-excitable. It should be appreciatedthat if this defibrillation fields is applied using the techniquesdescribed herein (small, local and synchronized to a local activationtime) the heart itself will not be defibrillated by the electric field.In one preferred embodiment of the invention, a locally defibrillatedportion of the heart is isolated by fences from the rest of the heart.

[0437]FIG. 3 illuminates one use of extending the refractory periods ofcardiac tissue. Segment 40 is a portion of a right atrium. An activationsignal normally propagates from an SA node 42 to an AV node 44. Severalcompeting pathways, marked 46A-46D, may exist between SA node 42 and AVnode 44, however, in healthy tissue, only one signal reaches AV node 44within its excitability window. In diseased tissue, several signalswhich have traveled in different paths may serially excite AV node 44even though they originated from the same action potential in the SAnode. Further, in atrial fibrillation, the entire right atrium may haverandom signals running through it. In a preferred embodiment of theinvention, electric fields are applied to a plurality of regions whichact as “fences” 48A and 48B. These fences are non-conducting toactivation signals during a particular, predetermined critical time,depending on the activation time of the electric fields. Thus, theactivation signal is fenced in between SA node 42 and AV node 44. It isknown to perform a surgical procedure with a similar effect (the “maze”procedure), however, in the surgical procedure, many portions of theright atrium need to be ablated to produce permanent insulating regions(fences). In the present embodiment of the invention, at least portionsof fences 48A and 48B may be deactivated after the activation signal haspassed, so that the atrium can contract properly.

[0438] In a preferred embodiment of the invention, a fence is appliedusing a linear array of bipolar electrodes. In another preferredembodiment of the invention, a fence is applied using two (slightly)spaced apart elongate wire electrodes of opposite polarity. Preferably,portions of the wire electrodes are isolated, such as segments 0.5 cmlong being isolated and segments 0.5 cm long being exposed.

[0439] Still another preferred embodiment of the invention relates totreating ventricular fibrillation (VF). In VF, a ventricle is activatedby more than one activation signal, which do not activate the ventriclein an orderly fashion. Rather, each segment of the ventricle is randomlyactivated asynchronously with the other segments of the ventricle andasynchronously with the cardiac cycle. As a result, no pumping action isachieved. In a preferred embodiment of the invention, a plurality ofelectrical fences are applied in the affected ventricle to damp thefibrillations. In general, by changing the window during which segmentsof the ventricle are sensitive to activation, a fibrillation causingactivation signal can be blocked, without affecting the naturalcontraction of the ventricle. In one embodiment of the invention, thefences are used to channel the activation signals along correctpathways, for example, only longitudinal pathways. Thus, activationsignals cannot move in transverse direction and transverse activationsignals will quickly fade away, harmlessly. Healthy activation signalsfrom the AV node will not be adversely affected by the fences.Alternatively or additionally, fences are generated in synchrony withthe activation signal from the AV node, so that fibrillation causingactivation signals are blocked. Further alternatively, entire segmentsof the ventricle are desensitized to the activation signals by applyinga positive potential to those segments deemed sensitive to fibrillation.

[0440] Dividing the heart into insulated segments using fences is usefulfor treating many types of arrhythmias. As used herein, the terminsulated means that conduction of the activation signal is blocked orslowed down or otherwise greatly reduced by deactivating portions of theheart conduction system. For example, many types of ventriculartachycardia (VT) and premature beats in the heart are caused by localsegments of tissue which generate a pacing signal. These segments can beinsulated from other segments of the heart so that only a small, localsegment is affected by the irregular pacing. Alternatively, thesediseased segments can be desensitized using an electric field, so thatthey do not generate incorrect activation signals at all.

[0441] Premature beats are usually caused by an oversensitive segment ofthe heart. By applying a local electric field to the segment, thesensitivity of the segment can be controlled and brought to similarlevels as the rest of the heart, solving the major cause of prematurebeats. This technique is also applicable to insensitive tissues, whichare sensitized by the application of a local electric field so that theybecome as sensitive as surrounding tissues.

[0442] It should be appreciated that it is not necessary to know theexact geometrical origin of an arrhythmia to treat it using the abovedescribed methods. Rather, entire segments of the heart can bedesensitized in synchrony with the cardiac cycle so that they do notreact before the true activation signal reaches them. Further, the heartcan be divided into isolated segments or fenced in without mapping theelectrical system of the heart. For example, electrodes can be insertedin the coronary vessels to create fences in the heart. These fences canblock most if not all of the irregular activation signals in the heartand still allow “correct” activation signals to propagate bysynchronizing the generation of these fences to the “correct” cardiacactivation profile. Alternatively or additionally, each isolated segmentis paced with an individual electrode. Alternatively, an array ofelectrodes may be implanted surrounding the heart so that it is possibleto individually control substantially any local portion thereof.

[0443] In an additional preferred embodiment of the present invention,segments of the heart are continuously controlled using an electricfield, so that their membrane potential at rest is below −60 mV. Belowthis level, the voltage-gated sodium channels cannot be opened by anactivation signal. It is not usually possible to clamp all of the cellsin a tissue segment to this voltage, so some of the cells in the tissuewill typically be excitable. However, it is known that hyperpolarizationcauses depletion of potassium ions in the extracellular spacessurrounding individual cardiac muscle cells, which will cause a generalreduction in the excitability of all the cells which share the sameextacellular spaces. As described, for example, in “K+Fluctuations inthe Extracellular Spaces of Cardiac Muscle: Evidence from the VoltageClamp and Extracellular K+—Selective Microelectrodes”, Cohen I and KlineR, Circulation Research, Vol. 50, No. 1, pp. 1-16, January 1982, thedisclosure of which is incorporated herein by reference. Thus, thereaction of the segments of the heart to an activation signal isreduced, has a longer delay and the propagation velocity in thosesegments is significantly reduced. Other resting potentials may affectthe opening of other voltage-gated channels in the cell.

[0444] Another preferred embodiment of the invention relates to cardiacsurgery. In many instances it is desirable to stop the pumping action ofthe heart for a few seconds or minutes necessary to complete a suture ora cut or to operate on an aneursym. Current practice is not veryflexible. In one method, the heart is bypassed with a heart-lung machineand the heart itself is stopped for a long period of time. This processis not healthy for the patient as a whole or for the heart itself and,often, serious postoperative complications appear. In another method,the heart is cooled down to reduce its oxygen consumption and it is thenstopped for a (non-extendible) period of a few minutes. The period isnon-extendible in part since during the stoppage of the heart the entirebody is deprived of oxygen. In these methods, the heart is usuallystopped using a cardioplesic solution. In a third method fibrillation isinduced in the heart. However, fibrillation is known to cause ischemia,due to the greatly increased oxygen demand during fibrillation and theblockage of blood flow in the coronary arteries by the contraction ofthe heart muscle. Ischemia can irreversibly damage the heart.

[0445] Cessation or reduction of the pumping activity of the heart maybe achieved using methods described herein, for example, fencing. Thus,in a preferred embodiment of the invention, the pumping action of theheart is markedly reduced using techniques described herein, repeatedlyand reversibly, for short periods of time. It should be appreciated thatdue to the simplicity of application and easy reversibility, stoppingthe heart using electrical control is more flexible than currentlypracticed methods. Electrical control is especially useful inconjunction with endoscopic heart surgery and endoscopic bypass surgery,where it is desirable to reduce the motion of small segments of theheart.

[0446] Another preferred embodiment of the present invention relates totreating ischemic portions of the heart. Ischemic portions, which may beautomatically identified from their injury currents using locallyimplanted sensors or by other electro-physiological characterization,may be desensitized or blocked to the activation signal of the heart.Thus, the ischemic cells are not required to perform work and may beable to heal.

[0447] U.S. provisional application No. 60/009,769 titled “CardiacElectromechanics”, filed on Jan. 11, 1996, by Shlomo Ben-Haim and MaierFenster, and its corresponding Israeli patent application No. 116,699titled “Cardiac Electromechanics”, filed on Jan. 8, 1996 by applicantBiosense Ltd., the disclosures of which are incorporated herein byreference, describe methods of cardiac modeling and heart option. Incardiac modeling, the distribution of muscle mass in the heart ischanged by changing the workload of segments of the heart or by changingthe plateau duration of action potentials at segments of the heart.These changes may be achieved by changing the activation profile of theheart. Plateau duration can be readily controlled using methods asdescribed hereinabove. Further, by controlling the conduction pathwaysin the heart, according to methods of the present invention, the entireactivation profile of the heart can be affected. In cardiac optimizationas described in these applications, the activation profile of the heartis changed so that global parameters of cardiac output are increased.Alternatively, local physiological values, such as stress, areredistributed to relieve high-stress locations in the heart. In apreferred embodiment of the present invention, the activation profilemay be usefully changed using methods as described hereinabove.

[0448] In order to best implement many embodiments of the presentinvention, it is useful to first generate an electrical, geometrical ormechanical map of the heart U.S. patent application Ser. No. 08/595,365titled “Cardiac Electromechanics”, filed on Feb. 1, 1996, by ShlomoBen-Haim, and two PCT applications filed in Israel, on even date as theinstant application, by applicant “Biosense” and titled “CardiacElectromechanics” and “Mapping Catheter”, the disclosures of which areincorporated herein by reference, describe maps and. methods and meansfor generating such maps. One particular map which is of interest is aviability map, in which the viability of different segments of hearttissue is mapped so as to identify hibernating and/or ischemic tissue.U.S. Pat. No. 5,391,199, U.S. patent application Ser. No. 08/793,859,filed on Aug. 19, 1994, titled “Means and Method for Remote ObjectPosition and Orientation Detection System” and PCT Patent applicationUS95/01103, now published as WO96/05768 on Feb. 29, 1996, thedisclosures of which are incorporated herein by reference, describeposition sensing means suitable for mounting on a catheter which isespecially useful for generating such maps. Such position sensing meansmay also be useful for correctly placing electrodes in the heart if theelectrodes are implanted using minimally invasive techniques such asthose using endoscopes, throactoscopes and catheters.

[0449] In one preferred embodiment of the invention, a map of the heartis used to determine which portions of the heart are viable, and thus,can be controlled to increase the cardiac output. Preferably, the entireactivation profile of the heart is taken into account when determiningto which portions of the heart a controlling field should be applied, tomaximize a parameter of cardiac output. The activation profile may alsodetermine the timing of the application of the field. A perfusion mapmay be used to access the blood flow to various portions of the heart.It is to be expected that increasing the contractility of a segment ofheart muscle also increases the oxygen demand of that segment.Therefore, it is desirable to increase the contractility only of thosesegments which have a sufficient blood flow. Possibly, the oxygendemands of other segments of the heart is reduced by proper controllingof the activation sequence of the heart.

[0450] Alternatively or additionally to mapping the perfusion and/orviability of the heart, the onset of controlling the heart may beperformed gradually. Thus, the cardiac blood supply has time to adapt tothe increased demand (if any) and to changes in supply patterns. Inaddition, the increase in demand will not be acute, so no acute problems(such as a heart attack) are to be expected as a result of thecontrolling. In one embodiment, the controlling is applied, at first,only every few heart beats, and later, every heart beat. Additionally oralternatively, the duration of a controlling pulse is graduallyincreased over a long period of time, such as several weeks.Additionally or alternatively, different segments are controlled fordifferent heart beats, to se the increased demand over a larger portionof the heart.

[0451] In an alternative preferred embodiment of the invention, thecontractility of the heart is controlled only during the day and notduring the night, as the cardiac demand during the day time is typicallygreater than during the night. Alternatively or additionally, thecontroller is used for a short time, such as 15 minutes, in the morning,to aid the patient in getting up.

[0452] Alternatively or additionally, a controlling electric field isapplied only once every number of beats (day and/or night). Furtheralternatively, the heart is controlled for a short period of timefollowing an acute ischemic event, until the heart recovers from theshock. One preferred controlling method which may be applied after aheart attack relates to preventing arrhythmias. Another preferredcontrolling is desensitizing infarcted tissue or reducing thecontractility of such tissue or electrically isolating such tissue so asto reduce its oxygen demands and increase its chance of healing.

[0453] One benefit of many embodiments of the present invention, is thatthey can be implemented without making any structural or other permanentchanges in the conduction system of the heart. Further, many embodimentsmay be used in conjunction with an existing pacemaker or in conjunctionwith drug therapy which affects the electrical conduction in the heart.In addition, different controlling schemes may be simultaneouslypracticed together, for example, controlling the heart rate andincreasing contractility in the left ventricle.

[0454] It must be appreciated however, that, by changing the activationprofile of the heart, some changes may be effected on the structure ofthe heart. For example, cardiac modeling, as described above, may resultfrom activation profile changes, over time.

[0455]FIG. 4A is a schematic diagram of an electrical controller 50, inoperation, in accordance with a preferred embodiment of the invention Amuscle segment 56, which is controlled by controller 50, is preferablyelectrified by at least one electrode 52 and preferably by a secondelectrode 54. Electrode 54 may be electrically floating. A sensor 58 maybe used to determine the local activation time of segment 56, as aninput to the controller, such as for timing the electrification of theelectrodes. Other additional or alternative local and/or global cardiacparameters may also be used for determining the electrification of theelectrodes. For example, the electrode(s) may be used to sense the localelectrical activity, as well known in the art. Alternatively, sensor 58is located near the SA node for determining the start of the cardiacrhythm. Alternatively, sensor 58 is used to sense the mechanicalactivity of segment 56, of other segments of the heart or for sensingthe cardiac output. Cardiac output may be determined using a pressuresensor or a flow meter implanted in the aorta. In preferred embodimentof the invention, sensor 58 senses the electrical state of the heart,controller 50 determines a state of fibrillation and electrifieselectrodes 52 and 54 accordingly.

[0456] Sensor 58 may be used for precise timing of the electrificationof electrodes 52 and 54. One danger of incorrect electrification of theelectrodes is that if the electrodes are electrified before anactivation front reaches segment 56, the electrification may inducefibrillation. In a preferred embodiment of the invention, sensor 58 isplaced between electrodes 52 and 54 so that an average activation timeof tissue at the two electrodes is sensed. It should be appreciated thatthe precise timing of the electrification depends on the propagationdirection of the activation front in the heart. Thus, if tissues atelectrodes 52 and 54 are activated substantially simultaneously, thecontrolling field can be timed to be applied shortly thereafter.However, if tissue at one electrode is activated before tissue at theother electrode, the delay time in electrifying the electrodes must belonger. Thus, the optimal delay time in electrifying an electrode afterthe local activation time is dependent, among other things, on theorientation of the electrodes relative to the activation front. Theconduction velocity of the activation front is affected in a substantialmanner by the orientation of the cardiac muscle fibers. Thus, theorientation of the electrodes relative to the muscle fiber directionalso has an effect on the optimal delay time.

[0457] In another preferred embodiment of the invention, localactivation time (and electrification of electrodes 52 and 54) isestimated, based on a known propagation time of the activation signal.For example, if sensor 58 is placed in the right atrium, a delay ofabout 120 msec may be expected between the sensing of an activationsignal at sensor 58 and the arrival of the activation signal atelectrodes 52 and 54. Such delays can also be estimated. Within a singlechamber, for example, it takes about 30-50 msec for the activation frontto cover all the left ventricle. A sensor 58 may be placed at a locationin the left ventricle which is excited relatively early by theactivation signal. In a preferred embodiment of the invention,activation propagation times between implanted sensors and electrodesare measured in at least one heart activation profile (such as at aresting heart rate) and are used to estimate a desired delay inelectrification of electrodes. It should be appreciated that, indiseased hearts, local conduction velocity may change substantially intime, thus, learning of and adaptation to the changes in localactivation are a desirable characteristic of controller 50. In apreferred embodiment of the invention, a particular state of arrythmia(or activation profile) is determined based on a parameter of the ECG,such as the morphology and/or the frequency spectrum of either anexternal or an internal ECG. Controller 50 determines the controllingprofile based on the determined state. In particular, delay times, asdescribed herein, may be associated with states, so that the exact delaytime for the activation may be decided in real-time for each state ofarrhythmia. Preferably, the delay times are precalculated and/or aredetermined during a learning state of controller 50, in which stage, anoptimal delay time is determined for a particular activation state andstored in association therewith.

[0458] Sensor 58 may be placed on the epicardium, on the endocardium or,in a preferred embodiment of the invention, sensor 58 is inserted intothe myocardium.

[0459]FIG. 4B shows an alternative embodiment of the invention, whereina heart segment 55 is controlled by a plurality of electrodes 59 whichare connected to a controller 57. The use of many electrodes enablesgreater control of both spatial and temporal characteristics of theapplied electric field. In one example, each one of electrodes 59 isused to determine its local activation. Controller 57 individuallyelectrifies electrodes 59 according to the determined activation.Preferably, the electrodes are activated in pairs, with current flowingbetween a pair of electrodes whose local activation time is known.

[0460] Different embodiments of the present invention will typicallyrequire different placement of the control electrodes. For example, someembodiments require a large area electrode, for applying an electricfield to a large portion of the heart. In this case, a net typeelectrode may be suitable. Alternatively, a large flat electrode may beplaced against the outside of the heart. Other embodiments require longelectrodes, for example, for generating fences. In this case, wires arepreferably implanted in the heart, parallel to the wall of the heart.Optionally, the electrodes may be placed in the coronary vessels outsidethe heart. In some aspects of the invention electrodes are placed sothat the field generated between the electrodes is parallel to thedirection in which activation fronts normally propagate in the heart, inothers, the field is perpendicular to such pathways.

[0461] In one preferred embodiment of the invention, a pacemaker isprovided which increases the cardiac output. A pacemaker activationpulse is usually a single pulse of a given duration, about 2 msec in aninternal pacemaker and about 40 msec in an external pacemaker. Inaccordance with a preferred embodiment of the invention, a pacemakergenerates a double pulse to excite the heart. A first portion of thepulse may be a stimulation pulse as known in the art, for example, 2 mA(milliamperes) constant current for 2 msec. A second portion of thepulse is a pulse as described herein, for example, several tens of mseclong and at a short delay after the first portion of the pacemakerpulse. Alternatively, a very long stimulation pulse may be used. Thistype of pacemaker preferably uses two unipolar electrodes, one at theapex of the heart and one at the top of the left ventricle (or the rightventricle if it the right ventricular activity is to be increased).

[0462] In a preferred embodiment of the invention, a controller isimplanted into a patient in which a pacemaker is already implanted. Thecontroller is preferably synchronized to the pacemaker by connectingleads from the controller to the pacemaker, by sensors of the controllerwhich sense the electrification of the pacemaker electrodes and/or byprogramming of the controller and/or the pacemaker.

[0463] In a preferred embodiment of the invention, the pacemaker adaptsto the physiological state of the body in which it is installed bychanging the heart's activity responsive to the physiological state. Thepacemaker can sense the state of the body using one or more of a varietyof physiological sensors which are known in the art, including, pHsensors, pO₂ sensors, pCO₂ sensors, blood-flow sensors, accelerationsensors, respiration sensors and pressure sensors. For example, thepacemaker can increase the flow from the heart in response to anincrease in pCO₂. Since the control is usually applied in a discretemanner over a series of cardiac cycles, this control may be termed acontrol sequence. The modification in the heart's activity may beapplied gradually or, preferably, in accordance with a predeterminedcontrol sequence.

[0464] In one aspect of the invention, target values are set for atleast one of the measured physiological variables and the pacemakermonitors these variables and the effect of the control sequence appliedby the pacemaker to determine a future control sequence. Once thediscrepancy between the target value and the measured value is lowenough, the control sequence may be terminated. As can be appreciated,one advantage of a cardiac controller over a pacemaker is that it cancontrol many aspect of the heart's activation profile. As a result, thecontroller can determine a proper tradeoff between several differentaspects of the activation profile of the heart, including, heart output,oxygenation of the cardiac muscle, contractile force of the heart andheart rate.

[0465] Another aspect of the invention relates to modifying the relationbetween the contraction of the left ventricle and the contraction of theright ventricle. In a healthy heart, increased contractility of the leftventricle is followed by increased contractility of the right ventricle,as a result of the increased output of the left ventricle, which causesan increase in the preload of the right ventricle. Decreased leftventricular output reduces the right ventricular output in a similarmanner. In some cases, such as pulmonary edema, it may be desirable tomodify the flow from one ventricle without a corresponding change in theflow from the other ventricle. This may be achieved by simultaneouslycontrolling both ventricles, one control increasing the flow form oneventricle while the other control decreases the flow from the otherventricle. This modification will usually be practiced for short periodsof tine only, since the vascular system is a closed system and, in thelog run, the flow in the pulmonary system is the same as in the generalsystem. In a preferred embodiment of the invention, this modification ispracticed by controlling the heart for a few beats, every certain periodof time.

[0466] Another aspect of the present invention relates to performing acomplete suite of therapies using a single device. A controller inaccordance with a preferred embodiment of the invention includes severaltherapies which it can apply to the heart, including for example,increasing, contractility, defibrillation, fencing, heart rate controland pacing. The controller senses (using physiological sensors) thestate of the body and decides an appropriate short-term therapy, forexample, defibrillation to overcome fibrillation, increasing the heartrate to increase the cardiac outflow or applying fences to restrain asudden arrhythmia. Additionally or alternatively, such a controller canchange the applied control sequence in response to long term therapeuticgoals. For example, if increasing contractility is used to increase themuscle mass in a portion of the heart, once a required muscle mass isreached, the control sequence may be stopped. This is an example of atherapeutic treatment affected by the controller. In another example, afew weeks after the device is implanted and programmed to increase thecardiac output to a certain target variable, the at variable may bechanged. Such a change may be mandated by an predetermined period oftime over which the heart adapts to the controller. One such adaptationis that the heart becomes stronger and/or more efficient. Another suchadaptation may be that the heart reduces its response to the controlsequence, so that a different control sequence may be required toachieve the same goals. In a preferred embodiment of the invention, thecontrol sequence is varied every certain period of time and/or when theresponse of the heart to the control sequence is reduced below apredetermined level.

[0467] In an alternative embodiment of the invention, a control deviceincludes a human operator in the loop, at least during a first stagewhere the controller must “learn” the distinctive aspects of aparticular hear/patient. At a later stage, the operator may monitor thetherapeutic effect of the controller on a periodic basis and change theprogramming of the controller if the therapeutic effect is not thatwhich the operator desires.

[0468] In an additional embodiment of the invention, the controller isnot implated in the body. Preferably, the control sequence is appliedusing one or more catheters which are inserted into the vascular system.Alternatively, electrodes may be inserted directly through the chestwall to the heart.

[0469] In another preferred embodiment of the invention, a controllingcurrent (or electric field) is applied from electrodes external to thebody. One inherent problem in external controlling is that thecontrolling current will usually electrify a large portion of the heart.It therefore important to delay the application of the current until theheart is refractory. One method of achieving this objective is to sensethe ECG using external electrodes. Preferably, an electrode array isused so that a local activation time in predetermined portions of theheart may be determined.

[0470] Another method of external controlling combines controlling withexternal pacing, thereby simplifying the task of properly timing thecontrolling pulse relative to the pacing pulse. In a preferredembodiment of the invention, the delay between the pacing pulse and thecontrolling pulse is initially long and is reduced until an optimumdelay is determined which gives a desired improvement in pumping anddoes not cause fibrillation.

[0471] Additionally or alternatively, the external pacemaker includes adefibrillator which applies a defibrillation pulse if the controllingpulse causes fibrillation.

[0472] It should be appreciated that pacemakers and controllers inaccordance with various embodiments of the present invention share manycommon characteristics. It is anticipated that combining the functionsof a controller and of a pacemaker in a single device will have manyuseful applications. However, several structural differences betweenpacemakers, defibrillators and controllers in accordance with manyembodiments of the present invention are notable.

[0473] One structural difference relates to the size and shape of theelectrodes. Pacemakers usually use bipolar activation electrodes orunipolar electrodes where the pacemaker case is the other electrode. Thedesign of the electrodes is optimized to enhance the contact between theelectrodes and the heart at a small area, so that the power drain in thepacemaker will be as low as possible. In a defibrillator, there is anopposite consideration, namely, the need to apply a very large amount ofpower to large areas of the heart without causing damage to the heart.In preferred embodiment of the present invention, small currents areapplied, however, it is desirable that the current will flow throughlarge portions of the cardiac tissue, in a controlled manner.

[0474] Another structural difference relates to the power supply.Pacemaker power supplies usually need to deliver a short (2 msec), lowpower, pulse once a second. Defibrillators usually need to deliver ashort (6-8 msec), high power, pulse or series of pulses at longintervals (days). Thus, pacemakers, usually drain the power from acapacitor having a short delay and which is directly connected to thebattery, while defibrillators usually charge up both a first and asecond capacitor so that they may deliver two sequential high-powerpulses. A controller in accordance with some embodiments of the presentinvention, is required to provide a long low power pulse once a second.Preferably, the pulse is longer than 20 msec, more preferably longerthan 40 msec and still more preferably, longer than 70 msec. Such apulse is preferably achieved using a slow-decay capacitor and/ordraining the power directly from a battery, via an constant current, aconstant voltage and/or a signal forming circuit. Preferably, theelectrodes used in a controller in accordance with the present inventionslowly release a steroid, to reduce inflammation at the electrodes pointof contact with the heart.

[0475] Another structural difference relates to the placement of theelectrodes. In a pacemaker, a single electrode is placed in the apex ofthe heart (in some pacemakers, one electrode per chamber, or sometimes,more than one). In a defibrillator the electrodes are usually placed sothat most of the heart (or the right atrium in AF defibrillators) isbetween the electrodes. In a controller according to some embodiments ofthe present invention, the electrodes are placed across a segment ofheart tissue, whose control is desired. Regarding sensing, manypacemakers utilize sensing in one chamber to determine a proper delaybefore electrifying a second chamber. For example, in a heart whose AVnode is ablated, the left ventricle is synchronized to the right atriumby a pacemaker which senses an activation front in the right atrium andthen, after a suitable delay, paces the left ventricle. It is not,however, a usual practice to sense the activation front in a chamber andthen pace the selfsame chamber after a delay. Even when such samechamber sensing and pacing is performed, the sensing and pacing areperformed in the right atrium and not the left ventricle. Further,sensing at the pacing electrode in order to determine a delay time forelectrification of the electrode is a unique aspect of some aspects ofthe present invention, as is sensing midway between two pacingelectrodes. Another unique aspect of some embodiments of the presentinvention is pacing in one chamber (the right atrium), sensing an effectof the pacing in another chamber (the left ventricle) and then pacingthe other chamber (the left ventricle). The use of multiple pairs ofelectrodes disposed in an array is another unique aspect of certainembodiments of the present invention.

[0476] Due to the wide range of possible signal forms for a controller,a preferred controller is programmable, with the pulse form beingexternally downloadable from a programmer. Telemetry systems for one-and two- directional communication between an imprinted pacemaker and anexternal programmer are well known in the art. It should be noted, thatvarious embodiments of the present invention can be practiced, albeitprobably less efficiently, by downloading a pulse form in accordancewith the present invention to a programmable pacemaker. In a preferredembodiment of the invention, such a programmer includes software foranalyzing the performance and effect of the controller. Since analysisof the performance of the controller may include information notprovided by the controller, such as an ultrasound image or an externalbody ECG, such software may be run from a separate computer.

[0477] It should be appreciated that a controller in accordance with thepresent invention is preferably personalized for particular patientbefore implantation therein. Alternatively or additionally, thepersonalizations may be performed by programming the device after it isimplanted. The heart of the patient is preferably mapped, as describedabove, in order to determine the preferred placement of the controlelectrodes and/or the sensing electrodes and/or in order to determinethe proper timings.

[0478] In one example, where the left ventricle is controlled, it isuseful to determine the earliest activated area in the left ventricle,for implantation of the sensing electrode. In another example, the heartis mapped to determine viable tissue portions which are suitable forimplantation of electrodes (such that current will flow between the twoelectrodes). In another example, the activation profile of the heart isdetermined so that it is possible to estimate propagation times betweenvarious portions of the heartland in particular, the pacing source(natural or artificial) and the controlling electrodes, In anotherexample, the propagation of the activation front in the heart isdetermined so that the proper orientation of the electrodes with respectto the front may be achieved and/or to properly locate the sensingelectrode (s0 with respect to the controlling electrodes. It is alsouseful to determine arrhythmias in the heart so as to plananti-arrhythmic treatment in accordance with the present invention.

[0479] In another example, the amount of increase in contractility isdetermined by the amount of live tissue between the controllingelectrodes. A viability map may be used to determine a segment of hearttissue having a desired mount of live tissue.

[0480] The timing of the activation of cardiac muscle relative to therest of the heart is an important factor in determining its contributionto the cardiac output. Thus, it is useful to determine the relativeactivation time of the segment of the heart which is to be controlled,prior to implanting the electrodes.

[0481]FIG. 5 shows an experimental setup designed and used to test someembodiments of the present invention. A papillary muscle 60, from amammalian species (in the first set of experiment, a guinea pig), wasconnected between a support 62 and a pressure transducer 64 in a mannersuch that isometric contraction could be achieved. Muscle 60 wasstimulated by a pair of electrodes 66 which were connected to a pulsedconstant current source 70. A pulse generator 74 generated constantcurrent pacing pulses for electrodes 66. A pair of electrodes 68 wereused to apply an electric field to muscle 60. A slave pulse generator76, which bases its timing on pulse generator 74, electrified electrodes68 via a pulsed constant current source 72. The force applied by themuscle was measured by transducer 64, amplified by an amplifier 78 anddrawn on a plotter 80. Pulse generator 74 selectably generated shortactivation pulses 500, 750, 1000 and 1500 msec (t1) apart for variableactivation of muscle 60, i.e., 2, 1.33, 1 and 0.66 Hz. Pulse generator76 generated a square wave pulse which started t2 seconds after theactivation pulse, was t3 seconds long and had a selected current (in mA)higher than zero (in amplitude).

[0482]FIG. 6A-6C are graphs showing some results of the experiments. Ingeneral, the results shown are graphs of the force of the musclecontractions after muscle 60 reaches a steady state of pulsedcontractions. FIG. 6A is a graph of the results under the followingconditions:

[0483] t1 (pacemaker pulse)=750 msec;

[0484] t2 (delay)=150 msec;

[0485] t3 (pulse duration)=100 msec; and

[0486] current=10 mA.

[0487] As can be seen, the force exerted by the muscle was increased bya factor of 2.5 when the controlling pulse (electrodes 68) was used asopposed to when electrodes 68 were not activated.

[0488]FIG. 6B is a graph of the force of muscle contractions under thefollowing conditions:

[0489] t1=1000 msec;

[0490] t2=20 msec;

[0491] t3=300 msec; and

[0492] current=7.5 mA.

[0493] As can be seen, the amplitude of the contractions is extremelyattenuated. When the polarity of the controlling signal was inverted,after a few contractions, the contractions of muscle 60 were almostcompletely attenuated.

[0494]FIG. 6C is a graph of the force of muscle contractions under thefollowing conditions:

[0495] t1=1000 msec;

[0496] t2=20 msec;

[0497] t3=300 msec; and

[0498] current 1 mA.

[0499] In this case, the effects of increasing the contractile force ofmuscle 60 remained for about two minutes after the electrification ofelectrodes 68 was stopped. Thus, the contraction of muscle 60 isdependent not only on the instantaneous stimulation and control but alsoon prior stimulation and control.

[0500] Using a similar experimental setup, additional experiments wereperformed, some on papillary muscles and some on cardiac septum musclesfrom the ventricles and atria walls. In these experiments, the testanimal was usually a rabbit, however, in one case a rat was used. Mostof these experiments used a DC constant current source which was incontact with the muscle, however, an electrical field scheme was alsotested, and yielded similar results. In the electric field scheme, theelectrodes were placed in a solution surrounding the muscle segment andwere not in contact with the muscle segment. The current used was 2-10mA. In a few experiments, no increase in contractile force was induced,however, this may be the result of problems with the electrodes(interaction with ionic fluids) and/or the current source, especiallysince Ag—AgCl electrodes, which tend to polarize, were used in theseexperiments. In general, many cycles of increases in contractility andreturn to a base line were performed in each experiment. In addition,the increases in contractility were repeatable in subsequentexperiments. These increases were obtained over a pacing range of 0.5-3Hz.

[0501] FIGS. 7A-7C summarize the results obtained in these furtherexperiments. It should be appreciated, that the time scales of theapplied pulse are strongly associated with the pacing rate and with theanimal species on which the experiment was performed. In theseexperiments, the pacing rate was usually about 1 Hz. Within the range of0.5-3 Hz the pulse form required for an increase in contraction force isnot substantially affected by the pacing rate. The intensities of thecurrents used in the experiments are affected by the electrode typesused, and possibly by the animal species, so that if other electrodetypes are used, different current intensities may be required for thesame effect. Ten experiments were performed on a left papillary muscle,of which 8 showed an increase in contractility due to an appliednon-excitatory current. Four experiments were performed on a rightpapillary muscle, of which three showed an increase in contractility.Two experiment were performed on left ventricular muscle, both showed anincrease in contractility. On the average, an increase in contractileforce of ˜75% was obtained. The range of increases was between 43% and228% depending on the exact experimental configuration.

[0502]FIG. 7A shows the effect of a delay in the onset of the appliedcurrent on the increase in contractile force. A small delay does notsubstantially affect the increase in contractile force. It should benoted that as the delay increases in duration, the increase incontractility is reduced. It is theorized that such a pulse, applied atany delay, affects the plateau and/or the refractory period. However,the increase in contractility is only possible for a window of timewhich is more limited than the entire activation cycle of a musclefiber.

[0503] Changing the polarity of the applied current sometimes affectedthe contractility. Usually, a first polarity generated an graterincrease in contractile force, while the other polarity generated alower increase than the first polarity. In some experiments, reversingthe polarity during an experiment decreased the contractile force, for ashort while or for the entire duration of the pulse, to a level lowerthan without any applied current. One possible explanation is thatpapillary muscle has a preferred conduction direction (which may not beas pronounced in ventricular tissue). Another explanation is artifactsrelating to the ionization of the electrodes used in the experiments.

[0504]FIG. 713 shows the effect of pulse duration on the increase incontractile force of a papillary muscle. A very short pulse, on theorder of 1 msec, does not substantially affect the contractile force. Ina pulse between about 1 msec and 20 msec the contractility increaseswith the duration. In a pulse of over 20 msec, the increase incontractile force as a function of pulse duration is reduced; and in apulse with over about 100 msec duration there is no apparent furtherincrease in the contractile force of an isolated papilary muscle.

[0505]FIG. 7C shows the effect of the current intensity on the increasein contractile force. It should be noted that above about 8 mA thecontractile force actually decreases below the baseline condition (whereno current was applied). It may be that this effect is related to theabove described theory of intracellular calcium stores, and that toomuch calcium in the cardiac muscle cell reduces the availability ofthese stores, and therefore, the cells contractility.

[0506] In addition to the above summarized results, several experimentalresults deserve special notice.

[0507] In one experiment, shown in FIG. 8A, a segment of a right atriumfrom a rabbit was allowed to set its own, intrinsic, pace (2-3 Hz). Anon-excitatory current which was a constant current of 2 mA was driventhrough the tissue, constantly, as shown. As a result, the self pacingrate of the segment increased, as did the contractility (after a first,short, reduction in force).

[0508] In a second, multi-step experiment, a right rabbit papillarymuscle was paced at 1.5 Hz. The applied current was constant at between2 and 4 mA (depending on the experimental step), in a pulse 70 msec longand no delay after the pacemaker pulse. The contractility increased bybetween 45% and 133% (depending on the step). The increasedcontractility was sustained at 3 mA for as long as two hours. Stoppingthe applied field caused a rapid return to the original (uncontrolled)contractile force. Re-application of the field repeated the previousresults.

[0509] In a third experiment, increasing the pulse duration of a 2 mAcurrent over the range 10 to 100 msec in a left rabbit papillary muscleincreased the contractile force; however, no effect on the duration ofthe muscle twitch was observed.

[0510]FIG. 5B is a series of graphs which shows an increase incontractility in several different cardiac muscle types (the horizontalbar indicates the application of a controlling electric field).

[0511] Two more experiments, not included in the above discussion, wereperformed on a papillary muscle. In these experiments, a triangularshaped pulse, having a duration of 120 msec and a peak of 5 mA, wasapplied with no delay after a standard pacing pulse (2 mA, 2 msec). Theincrease in contractility of the muscle was ˜1700%, from 10 mg to 178mg. The duration of the contraction increased from 220 msec to 260 msec.

[0512] In another series of experiments, a whole living heart wasremoved from a rabbit (1-2 Kg in weight) and controlled using methods asdescribed hereinabove. The apparatus for keeping the heart alive was anIsolated Heart, size 5, type 833, manufactured by Hugo Sachs Elektronik,Gruenstrasse 1, D-79232, March-Hugstetten, Germany. In theseexperiments, only the left ventricle is functional. The Pulmonary veinsare connected to a supply hose, in which supply hose there is a warm(˜37° C.) isotonic, pH balanced and oxygenated solution. The solution ispumped by the heart into the aorta. The heart itself is supplied withoxygen from the aorta, through the coronary arteries. The coronary veinsempty into the right ventricle, from which the solution drips out. Thesolution which drips out (coronary blood flow) can be measured bycollecting it in a measuring cup. Both the preload and the afterload ofthe vascular system can be simulated and preset to any desirable value.In addition, the afterload and preload can be measured using thisapparatus.

[0513] The heart was connected to an ECG monitor, a pacemaker and aprogrammable pulse generator. The electrodes for applied the fieldtypically had an area of between 2 and 3 cm². The left venticular prssre(LVP) was measured using a pressure probe inserted into the ventricle.The flow through the aorta was measured using an electromagneticflowmeter.

[0514] Various parameters, such as pH, PO₂, PCO₂ and temperature may bemeasured by attaching additional measurement devices. All themeasurement devices may be connected to a computer which collects, andpreferably analyzes the results.

[0515] A most notable experimental result was an increase in flow fromthe heart as a result of electrical control. Another notable result wasan increase in afterload as a result of the control.

[0516] Still another notable result was an increase in the developedleft ventricular pressure, in the heart, when electrical control wasapplied.

[0517] A summary of 26 experiments using an isolated heart is asfollows, in experiments an increase in cardiac output was observed,while in six experiments, no increase in cardiac output was observed.Possible reasons for the failure to increase cardiac output include,biological damage to the heart while it was being extracted from theanimal. In some cases, this damage is clear from the reduced cardiacoutput in one isolated heart as compared to a second, otherwise similar,rabbit heart. Other reasons include, incorrect placement of electrodes(over the right ventricle instead of over the left ventricle),encrustation of the electrodes with proteins and technical problems withthe equipment which delivers the controlling electric field. In 11experiments where the left ventricle was paced, the average increase incardiac output was 17% with a standard deviation of 11%. In eightexperiments where the right atrium was paced, the average increase was9±4%. In nine experiments, where the heart was not paced and acontrolling field was applied based on a sensing of local activationtimes, the increase was 7±2%. It should be noted that the number ofexperiments is over 26, since in some experiments two different pacingparadigms were tried.

[0518]FIG. 9 is a series of graphs showing the results of an experimentin which a 10 mA constant current pulse, having a duration of 20 msecand delayed 5 msec after the pacing of the heart, was applied. Two wireelectrodes were used to apply this pulse, one electrode was placed atthe apex of the heart overlaying the left ventricle and one electrodewas placed at the base of the left ventricle. The pacing was performedusing a bipolar electrode, also placed near the apex of the heart on theleft ventricle. The pacing rate was approximately 10% higher than thenormal pace. The pacing pulse was 2 msec long, 2 mA in amplitude and wasapplied at a frequency of ˜3.5 Hz. The application of the constantcurrent pulse is indicated in the Figure (and in the following ones) bya bar (filled or unfilled).

[0519] In this experiment, an increase in the afterload (the actualpressure developing in the Aorta) of about 5% and an increase in LVP(Left ventricle pressure) of about 3% were observed. The increase in LVPwas only in the end systole pressure, not in the end diastole pressure.An increase in flow of about 11% is clearly shown in FIG. 9. Theincrease in flow is very important since one of the main problems withpatients with congestive heart failure is a low cardiac flow.

[0520]FIG. 10 is a series of graphs showing the results of an experimentin which a 5 mA constant current pulse, having a duration of 80 msec anddelayed 2 msec after the pacing of the heart was applied. The wiring andpacing in this experiment were similar to the experiment described withreference to FIG. 9, except that carbon electrodes were used forapplying the constant current pulse.

[0521] In this experiment, a noticeable increase in afterload can bedetermined from the graph. An increase in LVP (Left ventricle pressure)of about 6% can also be observed. It should be noted that the increasein afterload is observed for both the diastolic pressure and thesystolic pressure, while inside the left ventricle, the pressureincrease is mainly in the systole. In fact, there is a slight reductionin diastolic pressure, which may indicate an increase in contractilityand/or an improvement in diastolic wall motion. An increase in flow ofseveral hundred percent is clearly shown in FIG. 10. It should be notedthat a healthy heart may be expected to have a flow of about 100 ml/min.The low initial flow (12 mL/min.) is probably a result of damage to theheart, such as ischemia.

[0522]FIG. 11 is a series of graphs showing the results of an experimentin which a 5 mA constant current pulse, having a duration of 20 msec anddelayed 2 msec after the local activation time at the ventricle wasused. The pacing and wiring in this experiment were similar to theexperiment described with reference to FIG. 9. A sensing electrode wasplaced on the left ventricle halfway between the two controllingelectrodes and the delay was measured relative to the local activationtime at the sensing electrode. The sensing electrode comprised two sideby side “J” shaped iridium-platinum electrodes. A pacing pulse wasapplied using an additional Ag—AgCl electrode at the apex of the heart.In this experiment, the sensing electrode is shut off for 200 msec afterthe local activation is sensed, so that the controlling pulse is noterroneously detected by the sensing electrode as a local activation.

[0523] In this experiment, an increase in the afterload and an increasein LVP were observed. The increase LVP was only evident in the endsystole pressure, not in the end diastole pressure. An increase in flowof about 23% is clearly shown in FIG. 11.

[0524]FIG. 12 is a series of graphs showing experimental results fromanother experiment, showing an significant increase in aortic flow andin aortic pressure. The pulse parameters were 5 mA, 70 msec duration anda 5 msec delay. Pacing and wiring are as in the experiment of FIG. 9.

[0525]FIG. 13 is a series of graphs showing experimental results fromrepeating the experiment of FIG. 12, showing that the increase in aorticflow is controlled by the electrification of the electrodes. Thus, whenthe electrification is stopped, the flow returns to a baseline value;when the electrification is restarted the flow increases again and whenthe electrification is stopped again, the flow returns to the baselinevalue.

[0526]FIG. 14 is a series of graphs showing experimental results fromanother experiment, in which the right atrium was paced at 3 Hz, ratherthan the left ventricle being paced at 3.5 Hz, as in previouslydescribed experiments. Pacing and wiring are similar to those in theexperiment of FIG. 11, except that the pacing electrodes are in theright atrium and the action potential is conducted from the right atriumto the left ventricle using the conduction pathways of the heart. Thepulse parameters are 5 mA for 20 msec, with no delay after sensing alocal action potential. The sensing electrode is shut off for 100 msecafter it senses the local action potential, to reduce the possibility ofidentifying the controlling pulse as a local activation potential. Inthis experiment, an increase in flow of 9% was observed.

[0527]FIG. 15 is a series of graphs showing experimental results fromanother experiment, similar to the experiment of FIG. 14, except thatinstead of using two controlling electrodes, four controlling electrodeswere used. The controlling electrodes were arranged in a square, withthe sensing electrode at the center of the square. One pair ofcontrolling electrodes comprised an electrode at the apex of the leftventricle and an electrode at the base. The other two electrodes werelocated in the halfway between the base and the apex of the leftventricle and near the right ventricle (at either side of the leftventricle). The applied pulse was 10 mA for 20 msec at a delay of 2msec. Both pairs of electrodes are electrified simultaneously.

[0528] In this experiment, an increase in the afterload and an increasein end-systolic LVP were observed. In addition, a decrease inend-diastolic LVP was observed. An increase in flow of about 7% is alsoshown in FIG. 15.

[0529]FIG. 16 is a series of graphs showing experimental results fromanother experiment, similar to the experiment of-FIG. 14, except that nosensing electrode is used. Rather, an activation signal propagation timeis estimated for calculation of the desired delay between pacing theright atrium and controlling the left atrium. The activation propagationtime is estimated by measuring the time between the pacing signal andthe contraction of the left ventricle. The delay time is 5 msec morethan the calculated average propagation time and was about 140 msec. Inthis experiment, an increase in the afterload and an increase in LVPwere observed. An increase in flow of about 14% is also shown in FIG.16.

[0530]FIG. 17 is a series of graphs showing experimental results fromanother experiment, similar to the experiment of FIG. 14, except that nopacing electrodes are used. Rather, the isolated heart is allowed topace at its own rhythm. The pulse parameters are a 20 msec long pulse of10 mA applied to both pairs of electrodes simultaneously, at a delay of2 msec after the sensing electrode senses a local activation potential.

[0531] In this experiment, an increase in the afterload and an increasein LVP were observed. An increase in flow of about 7% is also shown inFIG. 17. It should be noted that the baseline output of the heart wasabout 110 ml/min which indicates an output of a healthy heart.

[0532]FIG. 18A is a series of graphs showing experimental results fromanother experiment in which the heart was made ischemic. The wiring issimilar to that of FIG. 17, except that only one pair of controllingelectrodes was used, one at the apex and one at the base of the leftventricle. The ischemia was designed to simulate a heart attack bystopping the flow of oxygenated solution to the coronary arteries forabout ten minutes. After the flow of oxygenated solution was restarted areduction in the cardiac output from 100 m/min. to 38 ml/min. wasobserved. In addition, various arrhythmias in the activation of theheart were observed as a result of the ischemic incident. Controllingthe heart, using a 20 msec pulse of 5 mA delayed 2 msec after thepacing, increased the flow by 16%. The sensing was blocked for between100 and 200 msec after the sensing of a local activation. It should benoted that the controlling sequence worked even though the heart wasarrhythmic.

[0533] One interesting result of the isolated heart experiments relatesto pulse forms which do not induce fibrillation in the heart. It wasdetermined that the pulse should not extend more than about half theduration of the left ventricle pressure wave (in this experimentalsetup, the pressure wave is measured, not electrical activity). Inaddition, a small delay (˜5 msec) between the pacing and the pulse alsoappears to protect against fibrillation when the left ventricle ispaced.

[0534]FIG. 18B is a series of graphs showing experimental results fromanother experiment in which the output of the heart was reduced. Theheart was paced at the right atrium, using a pacing scheme similar tothat of the experiment of FIG. 14. A controlling current was applied tothe left ventricle using carbon electrodes. The controlling current wasa 20 msec pulse of 5 mA amplitude applied at a delay of 30 msec afterthe pacing at the right atrium. Flow, LVP and Aortic pressure were allnoticeably reduced as a result of this pulse.

[0535] Reducing the cardiac output is desirable in severalcircumstances, one of which is the disease “Hyperthropic Cardiomyopathy(HOCM).” This controlling scheme reduces the output of the leftventricle and the resistance against which the left ventricle isworking, both of to which are desirable for the above disease. It ishypothesized that the early controlling pulse (it is applied before theactivation front from the right atrium reaches the left ventricle) worksby extending the refractory periods of some of the cells in the leftventricle, thereby reducing the number of cells which take part in thesystole and reducing the cardiac output. Presumably, different cells areaffected each cardiac cycle. Alternatively, it may be that the precisedelay determines which cells are affected. It is known to shorten the AVinterval in order to improve the conditions of patients with HOCM.However, in the art, the entire ventricle is paced, albeit earlier. Inthe embodiment of the invention just described, the early appliedelectric filed does not cause an early contraction of the ventricle, anddoes not effectively shorten the AV interval, as done in the art.

[0536]FIGS. 19 and 20 show the results of experiments performed on liveanimals on an in-vivo heart. In the experiment whose results are shownin FIG. 19, a live 2.5 Kg rabbit was anesthetized using a venous accessin its pelvic region with its chest opened to expose the heart. Thepericardium of the heart was removed to provide direct contact betweenthe heart and electrodes. The heart was paced via the left ventricleusing a pair of titanium electrodes and the controlling current wasapplied using a pair of carbon electrodes. As in previous experiments,the pacing was applied at the apex of the left ventricle and thecontrolling electrodes were applied one at the base and one at the apexof the left ventricle. The rabbit was artificially respirated andliquids were supplied through the venous access. A blood-pressurecatheter was inserted into the left femoral artery to measure thearterial blood pressure. The right carotid artery was exposed and amagnetic flowmeter was placed thereon to measure the flow in the carotidartery. The flow in a carotid artery was measured rather than the flowin the aorta for reasons of convenience. However, it should be notedthat the carotid arteries have a feedback mechanism by which theyattempt to maintain a constant blood supply to the brain by contractingthe artery if the flow is too high.

[0537] The controlling signal was a 40 msec pulse having a amplitude of4 mA and applied 5 msec after the pacing signal. The pacing signal was a2 msec, 2 mA pulse at 5 Hz. An increase in flow in the right carotidartery of between 54 and 72% was observed during the application of thecontrolling signal.

[0538] The experiment whose results are shown in FIG. 20 had a similardesign to the experiment of FIG. 19, except that the flow was measuredusing an ultrasonic flowmeter. The controlling current was a 20 msecpulse having an amplitude of 2 mA and delayed 5 msec from the pacingsignal (which was the same as in the experiment of FIG. 19). Both anincrease in flow and in blood pressure were observed in this experiment.

[0539]FIG. 21 shows the results of an experiment in an in-vivo heart inwhich the heart was not paced. It is similar to the experiments of FIGS.19 and 20, in that blood pressure was measured in the right femoralartery and flow was measured, using an ultrasonic flowmeter, through theright carotid art. The controlling pulse was applied usingtitanium-nitride electrodes, at the apex and at the base of the leftventricle. An iridium-platinum bi-polar electrode was placed at the apexof the left ventricle to sense the arrival of an activation front fromthe SA node of the heart. The controlling current was a 20 msec pulse,having an amplitude of 2 mA and applied 30 msec after the activationfront was sensed. Increases in both the blood flow and the bloodpressure were observed in his experiment.

[0540]FIGS. 22 and 23 show the results of two experiments, similar tothe experiment of FIG. 21, in which the flow parameter was measured onthe ascending aorta. The heart of a 1.1 Kg rabbit was exposed and asensing electrode (bipolar) was inserted, using a needle, into the apexof the heart. Two carbon electrodes were used to apply a controllingpulse to the heart, at the apex and the base of the left ventricle. Theheart was not paced, it intrinsic pace was about 5 Hz. The control pulsewas a 5 mA in amplitude and had a duration of 40 msec. There was nodelay between the sensing of an activation front at the sensingelectrodes and application of the pulse.

[0541]FIG. 22 shows an increase of about 11% in the aortic flow. FIG.23, which shows the results of a repetition of the same experiment onthe same animal at a later time, shows an increase of about 8%.

[0542] Although the present invention has been described mainly withreference to the heart, it should be appreciated that preferredembodiments of the present invention may be applied to other types ofexcitable tissue. In one example, skeletal muscle and smooth muscle canbe controlled as described hereinabove. It should however beappreciated, that most muscles have different ion channels and differentresting potentials than cardiac muscle, so that the general principlesmust be adapted to the individual physiology. In addition, the effectsin a skeleton muscle may be due to recruitment of muscle fibers.Further, the present invention may be applied to neural tissue. Forexample, epileptic fits and tetanization may be controlled by dampingthe excitability of neural tissue, as described above. Alternatively,electrical control may be used in conjunction with electricalstimulation of denervated or atrophied muscles to increase the precisionof stimulation. Additionally or alternatively, electrical control may beused to block or enhance conduction of stimuli along nervous pathways,for example, to control pain.

[0543] In a preferred embodiment of the invention, epileptic fits arecontrolled by suppressing Golgi cells, thus, reducing the excitabilityof associated neural tissues by reducing the amount of availablecalcium.

[0544] The above description of the present invention focuses onelectrical control of cardiac tissue. However, since some aspect of thecontrol may be related to calcium ion transport in the cardiac tissue,non-electrical control is also possible. One major advantage ofnon-electrical control is that even though incorrect synchronization ofthe control to the cardiac cycle may reduce the cardiac output, there islittle or no danger of fibrillation. In one preferred embodiment of thepresent invention light is used to control calcium transport in portionsof the heart. Laser light may be used to affect the calcium transportdirectly. Alternatively, a light activated chelator, which is introducedinto at least some of the cells in a heart, may be activated by regularlight to change the availability (increasing or reducing) of calcium inthe illuminated cells. A controller in accordance with this embodimentof the invention, will include at least a light source and a lightguide, preferably an optical fiber, which will convey the light todesired portions of the heart. Preferably, the optical fiber is asilicon-rubber optical fiber which is resistant to breakage.Alternatively, the controller comprises a plurality of light emittingelements, such as laser diodes, placed directly on the controlledtissue. Further alternatively, the light is provided by a catheterinserted into the heart and either floating in the heart or fixed to theheart wall. The controller preferably includes an ECG sensor for sensinglocal and/or global activation times, as described above.

[0545] One limitation of light over electrical current is that unlessthe body tissues are transparent to the particular wavelength used,light can only have a very localized effect, a global effect requiresmany light sources, which is invasive. One type of less invasive lightsource which may be useful is an optical fiber having a partiallyexposed sheath. Light will leak out of the fiber at the exposedportions, so a single fiber can illuminate a plurality of localities.

[0546] In an alternative embodiment of the invention, electromagneticradiation at low and/or radio frequencies is used to affect calciumtransport in the cardiac tissue. Several methods may be used to provideelectromagnetic radiation. In one method, the entire heart isirradiated, preferably in synchrony with a sensed ECG of the heart. Inanother method, a phased array is used to aim the radiation at theheart. As noted above, the non-arrhythmic heart substantially repeatsits position each cycle, so there is no problem of registration betweenan external source and a portion of the heart. In yet another method, animplanted device includes a plurality of antennas, each disposedadjacent to a portion of tissue to be controlled. The antennas may bepowered by a central source. Alternatively, the antenna are concentrateexternally applied radiation. Further alternatively, the antennas arecoils which generate localized AC magnetic fields. It should be notedthat electromagnetic radiation appears to be suitable for reducingcalcium availability, which makes it suitable for reducing the oxygendemands of an infracted tissue after a heart attack. In embodimentsusing electromagnetic-radiation as in light and electric current, theremay be a long term reduction in the effectiveness of the controller dueto adaptation mechanisms of the heart. Thus, in a preferred embodimentof the invention, the controller is not used continuously, withpreferred rest periods between uses, being minutes, hours, days or weeksdepending on the adaptation of the heart.

[0547] In a preferred embodiment of the invention, two or more controlmodalities are applied simultaneously, for example, applying both lightradiation and electric fields. Alternatively, these modalities may beapplied alternately, so as to cope with adaptation mechanisms.Preferably, each modality is applied until adaptation sets in, at whichpoint the modality is switched.

[0548] Although the present invention has been described using a limitednumber of preferred embodiments, it should be appreciated that it iswithin the scope of the invention to combine various embodiments, forexample, increasing the contractility of the left ventricle, whilecontrolling the heart rate in the right atrium. It is also in the scopeof the present invention to combine limitations from variousembodiments, for example, limitations of pulse duration and pulse delayrelative to an activation or limitations on electrode type and electrodesize. Further, although not all the methods described herein are to beconstrued as being performed using dedicated or programmed controllers,the scope of the invention includes controllers which perform thesemethods. In some cases, limitations of preferred embodiments have beendescribed using structural or functional language for clarity, however,the scope of the invention includes applying these limitations to bothapparatus and methods.

[0549] It will be appreciated by a person skilled in the art that thepresent invention is not limited by what has thus fir been particularlydescribed. Rather, the present invention is limited only by the claimswhich follow.

1. A method of modifying the activity of the heart, or of a portionthereof, comprising applying to said heart, or portion thereof anon-excitatory electric field of a magnitude, shape, duty cycle, phase,frequency and duration suitable to obtain the desired change, whereinsaid field is applied at a time such as to be unable to generate apropagating action potential.
 2. A method according to claim 1, whereinthe portion of the heart to which the non-excitatory field is applied isa heart chamber.
 3. A method according to claim 1, wherein thenon-excitatory electric field comprises an alternated current electricfield.
 4. A method according to claim 1, wherein the non-excitatoryelectric field has a temporal envelope selected from exponentialtemporal envelope, sinusoidal temporal envelope, square temporalenvelope, triangular temporal envelope, ramped temporal envelope,sawtooth temporal envelope and biphasic temporal envelope.
 5. A methodaccording to claim 1, wherein the desired change is an increase of theforce of contraction of said heart, heart chamber or portion thereof. 6.A method according to claim 1, wherein the desired change is an increaseof the stroke volume of a chamber of the heart.
 7. A method according toclaim 1, wherein the desired change is an increase of the output flow ofa chamber of the heart.
 8. A method according to claim 1, wherein thedesired change is a change in pressure.